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Lee J, Kim J, Sin JI. B16 melanomas evade antitumor immunity by the loss of epitope presentation and the acquisition of tumor resistance to granzyme B. Cell Immunol 2021; 367:104394. [PMID: 34198057 DOI: 10.1016/j.cellimm.2021.104394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/20/2021] [Accepted: 06/05/2021] [Indexed: 12/25/2022]
Abstract
Melanomas exhibit the highest rate of heterogeneity among cancer cell types. In this study, we tested the two types of B16 melanoma cells (B16-S0-1 and B16-S1-1) showing resistance to antitumor immunity. These cells expressed Trp2 protein. Contrary to B16 and B16-S0-1 cells, B16-S1-1 cells failed to stimulate IFN-γ responses in Trp2-specific CD8+ T cells, suggesting that B16-S1-1 cells may have lost the ability to present antigen to Ag-specific CTLs in the context of MHC class I molecules. However, B16-S0-1 cells exhibited active Stat3 and decreased Bcl-2 expression, which were found to be not associated with immune escape. B16-S0-1 cells were more resistant to granzyme B-mediated caspase activation and apoptosis than B16 cells. Thus, these data show that B16 cells escape antitumor immune responses through the loss of epitope presentation to CTLs and the acquisition of tumor cell resistance to granzyme B-mediated caspase activation.
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Affiliation(s)
- Jaeyeon Lee
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea; Interdisciplinary Graduate Program in BIT Medical Convergence, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea
| | - Jiyoon Kim
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea
| | - Jeong-Im Sin
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea; Interdisciplinary Graduate Program in BIT Medical Convergence, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
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2
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Muraki R, Morita Y, Ida S, Kitajima R, Furuhashi S, Kiuchi R, Takeda M, Kikuchi H, Hiramatsu Y, Sakaguchi T, Kasuya A, Hotta Y, Takeuchi H. Multimodal therapy with surgery and adjuvant nivolumab for late-onset multiple liver metastases of choroidal malignant melanoma: a case report. Surg Case Rep 2020; 6:187. [PMID: 32737694 PMCID: PMC7394981 DOI: 10.1186/s40792-020-00948-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Choroidal malignant melanoma is the most common primary malignant tumor of the eye in adults. Prognosis after recurrence of this disease has been dismal because of the absence of an effective therapy. However, resection of recurrent foci and a subsequent treatment with immune-checkpoint inhibitor may improve the prognosis after recurrence of this disease. This study presents a case of late-onset liver metastases of choroidal malignant melanoma, successfully treated with hepatectomy and postoperative adjuvant nivolumab. CASE PRESENTATION A 53-year-old woman had undergone left ocular enucleation because of choroidal malignant melanoma 13 years prior to admission. She visited a nearby clinic with complaints of epigastric pain. She was referred to our hospital because a giant liver tumor was observed on abdominal ultrasonography. Enhanced computed tomography revealed multiple liver tumors in the right lobe, 49 mm in diameter with ring enhancement in subsegment (S) 5/6, and 14 and 8 mm without any enhancement in S7 and S5, respectively. On magnetic resonance imaging, the main tumor showed high intensity on T1-weighted with fat suppression, suggesting melanin deposition. Based on the diagnosis of multiple liver metastases of choroidal malignant melanoma, right hepatectomy and regional lymphadenectomy were performed. She was discharged without postoperative complications. Histological examination revealed that all tumors were metastatic malignant melanoma. She was treated with nivolumab postoperatively, and no recurrences were observed during 22 months of follow-up. CONCLUSIONS Aggressive surgery plus adjuvant nivolumab appears to be a promising treatment for choroidal malignant melanoma with late-onset liver metastases.
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Affiliation(s)
- Ryuta Muraki
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
| | - Yoshifumi Morita
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Shinya Ida
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Ryo Kitajima
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Satoru Furuhashi
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Ryota Kiuchi
- Department of Gastroenterological Surgery, Iwata City Hospital, Iwata, Japan
| | - Makoto Takeda
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Hirotoshi Kikuchi
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Yoshihiro Hiramatsu
- Department of Perioperative Functioning Care & Support, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takanori Sakaguchi
- Department of Gastroenterological Surgery, Iwata City Hospital, Iwata, Japan
| | - Akira Kasuya
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshihiro Hotta
- Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
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Park HR, Jo SK, Cho HH, Jung U. Synergistic Anti-cancer Activity of MH-30 in a Murine Melanoma Model Treated With Cisplatin and its Alleviated Effects Against Cisplatin-induced Toxicity in Mice. In Vivo 2020; 34:1845-1856. [PMID: 32606154 DOI: 10.21873/invivo.11979] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/10/2020] [Accepted: 04/12/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Although cisplatin is an effective anticancer drug, its toxic effects on normal tissues limit its use. We developed a herbal formula, MH-30, with increased fat-soluble polyphenols by improving the manufacturing method of HemoHIM. In this study, we examined whether the combination of MH-30 with cisplatin exerts synergistic antitumor effect while it reduces cisplatin-induced toxicities. MATERIALS AND METHODS MH-30 was produced by adding the ethanol-insoluble fraction to its extract after decocting herbs in 30% ethanol and water. We used a melanoma-bearing mice model to investigate synergistic anticancer effects. The NK cell activity and cytokine levels were measured by Cr51-release assay and ELISA. The AST, ALT, BUN, and creatinine levels were estimated in the serum. RESULTS MH-30 effectively inhibited melanoma growth in vitro. Furthermore, MH-30 had a synergistic effect in combination with cisplatin on melanoma growth inhibition in vitro and in vivo. In melanoma-bearing mice, cisplatin alone decreased the activity of NK cells and the levels of IL-2 and IFN-γ, which were effectively restored by the combination of MH-30 with cisplatin. Combined treatment with MH-30 and cisplatin significantly inhibited the cisplatin-induced increase in the levels of AST, ALT, BUN, and creatinine. CONCLUSION Combination of MH-30 with cisplatin may be a beneficial anticancer treatment with reduced adverse effects.
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Affiliation(s)
- Hae-Ran Park
- Radiation Research Division, Korea Atomic Energy Research Institute (KAERI), Jeongeup, Republic of Korea
| | - Sung-Kee Jo
- Radiation Research Division, Korea Atomic Energy Research Institute (KAERI), Jeongeup, Republic of Korea
| | - Hyang-Hee Cho
- Radiation Research Division, Korea Atomic Energy Research Institute (KAERI), Jeongeup, Republic of Korea
| | - Uhee Jung
- Environmental Safety Evaluation Research Division, Korea Atomic Energy Research Institute (KAERI), Jeongeup, Republic of Korea
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Zhang W, Gao J, Cheng C, Zhang M, Liu W, Ma X, Lei W, Hao E, Hou X, Hou Y, Bai G. Cinnamaldehyde Enhances Antimelanoma Activity through Covalently Binding ENO1 and Exhibits a Promoting Effect with Dacarbazine. Cancers (Basel) 2020; 12:cancers12020311. [PMID: 32013122 PMCID: PMC7072165 DOI: 10.3390/cancers12020311] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 01/19/2020] [Accepted: 01/27/2020] [Indexed: 12/28/2022] Open
Abstract
At present, melanoma is a common malignant tumor with the highest mortality rate of all types of skin cancer. Although the first option for treating melanoma is with chemicals, the effects are unsatisfactory and include poor medication response and high resistance. Therefore, developing new medicines or a novel combination approach would be a significant breakthrough. Here, we present cinnamaldehyde (CA) as a potential candidate, which exerted an antitumor effect in melanoma cell lines. Chemical biology methods of target fishing, molecular imaging, and live cell tracing by an alkynyl-CA probe revealed that the α-enolase (ENO1) protein was the target of CA. The covalent binding of CA with ENO1 changed the stability of the ENO1 protein and affected the glycolytic activity. Furthermore, our results demonstrated that dacarbazine (DTIC) showed a high promoting effect with CA for antimelanoma both in vivo and in vitro. The combination improved the DTIC cell cycle arrest in the S phase and markedly impacted melanoma growth. As a covalent inhibitor of ENO1, CA combined with DTIC may be beneficial in patients with drug resistance in antimelanoma therapy.
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Affiliation(s)
- Weiyi Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Jie Gao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Chuanjing Cheng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Man Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Wenjuan Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Xiaoyao Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Wei Lei
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
| | - Erwei Hao
- Collaborative Innovation Center of Research on Functional Ingredients from Agricultural Residues, Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese medicine, Nanning 530200, China; (E.H.); (X.H.)
| | - Xiaotao Hou
- Collaborative Innovation Center of Research on Functional Ingredients from Agricultural Residues, Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese medicine, Nanning 530200, China; (E.H.); (X.H.)
| | - Yuanyuan Hou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
- Correspondence: (Y.H.); (G.B.)
| | - Gang Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China; (W.Z.); (J.G.); (C.C.); (M.Z.); (W.L.); (X.M.); (W.L.)
- Correspondence: (Y.H.); (G.B.)
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Aghayan DL, Kazaryan AM, Fretland ÅA, Sahakyan MA, Røsok BI, Bjørnbeth BA, Edwin B. Laparoscopic liver resection for metastatic melanoma. Surg Endosc 2017; 32:1470-1477. [PMID: 28916919 DOI: 10.1007/s00464-017-5834-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 08/20/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Stage IV metastatic melanoma carries a poor prognosis. In the case of melanoma liver metastasis (MLM), surgical resection may improve survival and represents a therapeutic option, with varying levels of success. Laparoscopic liver resection (LLR) for metastatic melanoma is poorly studied. The aim of this study was to analyze the outcomes of LLR in patients with MLM. MATERIALS AND METHODS Between April 2000 and August 2013, 11 (1 cutaneous, 9 ocular and 1 unknown primary) patients underwent LLR for MLM at Oslo University Hospital-Rikshospitalet and 13 procedures in total were carried out. Perioperative and oncologic outcomes were analyzed. Postoperative morbidity was classified using the Accordion classification. Kaplan-Meier method was used for survival analysis. RESULTS A total of 23 liver specimens were resected. The median operative time was 137 (65-470) min, while the median blood loss was less than 50 (<50-900) ml. No intraoperative unfavorable incidents and 30-day mortality occurred. Median follow-up was 33 (9-92) months. Ten patients (91%) developed recurrence within a median of 5 months (2-18 months) and two patients underwent repeat LLR for recurrent liver metastases. One-, three-, and five-year overall survival rates were 82, 45 and 9%, respectively. The median overall survival was 30 (9-92) months. CONCLUSION Perioperative morbidity and long-term survival after LLR for MLM seems to be comparable to open liver resection. Thus, LLR may be preferred over open liver resection due to the well-known advantages of laparoscopy, such as reduced pain and improved possibility for repeated resections.
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Affiliation(s)
- Davit L Aghayan
- The Intervention Centre, Oslo University Hospital - Rikshospitalet, Pb. 4950 Nydalen, 0424, Oslo, Norway.
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Airazat M Kazaryan
- The Intervention Centre, Oslo University Hospital - Rikshospitalet, Pb. 4950 Nydalen, 0424, Oslo, Norway
- Department of Gastrointestinal Surgery, Akershus University Hospital, Lørenskog, Norway
| | - Åsmund Avdem Fretland
- The Intervention Centre, Oslo University Hospital - Rikshospitalet, Pb. 4950 Nydalen, 0424, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Mushegh A Sahakyan
- The Intervention Centre, Oslo University Hospital - Rikshospitalet, Pb. 4950 Nydalen, 0424, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Bård I Røsok
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Bjørn Atle Bjørnbeth
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Bjørn Edwin
- The Intervention Centre, Oslo University Hospital - Rikshospitalet, Pb. 4950 Nydalen, 0424, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Zheng AW, Jia DD, Xia LM, Jin G, Wu H, Li T. Impact of carboplatin plus paclitaxel combined with endostar against A375 melanoma cells: An in vitro and in vivo analysis. Biomed Pharmacother 2016; 83:1321-1326. [DOI: 10.1016/j.biopha.2016.08.047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 07/29/2016] [Accepted: 08/18/2016] [Indexed: 11/16/2022] Open
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Abstract
Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various chemotherapy combinations in order to expand on the clinical responses achieved with single-agent dacarbazine, but these have not demonstrated an improvement in overall survival. Similar objective responses were observed with the combination of carboplatin and paclitaxel as were seen with single-agent dacarbazine. The combination of chemotherapy and immunotherapy, known as biochemo-therapy, has shown high clinical responses; however, biochemo-therapy has not been shown to improve overall survival and resulted in increased toxicities. In contrast, palliation and long-term responses have been observed with localized treatment with isolated limb perfusion or infusion in limb-isolated disease. Although new, improved therapeutic options exist for first-line management of advanced-stage melanoma, chemotherapy may still be important in the palliative treatment of refractory, progressive, and relapsed melanoma. We review the various chemotherapy options available for use in the treatment and palliation of advanced-stage melanoma, discuss the important clinical trials supporting the treatment recommendations, and focus on the clinical circumstances in which treatment with chemotherapy is useful.
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Page AJ, Weiss MJ, Pawlik TM. Surgical management of noncolorectal cancer liver metastases. Cancer 2014; 120:3111-3121. [DOI: 10.1002/cncr.28743] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Andrew J. Page
- Department of Surgery; Johns Hopkins Hospital; Baltimore Maryland
| | - Matthew J. Weiss
- Department of Surgery; Johns Hopkins Hospital; Baltimore Maryland
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Tang MR, Wang YX, Guo S, Han SY, Wang D. CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway. Apoptosis 2013; 17:927-37. [PMID: 22538441 DOI: 10.1007/s10495-012-0727-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
In this work, we studied the effects of CUB and Sushi multiple domains 1 gene (CSMD1) expression in A375 melanoma cells in vivo and in vitro. CSDM1 expression decreased proliferation and migration, and increased apoptosis and G(1) arrest in A375 cells in vitro. Expression of CSDM1 in established xenografted tumors decreased tumor size and weight, and decreased the density of intratumor microvessels. The survival rate of mice with tumors expressing CSMD1 was significantly higher than mice with tumors that did not express CSDM1. These results confirm the role of CSDM1 as a tumor suppressor gene in melanoma cells. Furthermore, we found that CSMD1 can interact with Smad3, activate Smad1, Smad2, and Smad3, and increase the expression of Smad4. These results might prove helpful for the development of novel therapies for melanoma treatment.
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Affiliation(s)
- Ming-Rui Tang
- Department of Plastic Surgery, The First Hospital of China Medical University, Nanjing North Street 155 Heping District, Shenyang City, 110001, China.
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Abstract
The recent past has witnessed unprecedented clinical progress in the treatment of advanced malignant melanoma through targeting of mutant BRAF in approximately 50% of patients and immune check point blockade in all patients. As has been well documented, responses to targeted therapy are of limited duration, and rates of clinical benefit to immunotherapy are modest. Given these factors, palliation of patients with chemotherapy remains an essential aspect of melanoma oncology. Many chemotherapeutics (and combinations with other agents, such as immunotherapy) have been evaluated in melanoma, although no chemotherapy regimen has been documented to provide an overall survival benefit in a prospective, randomized, well-controlled phase III study. We provide an overview of the development of the most common chemotherapy regimens for melanoma, discuss the clinical trial evidence supporting and contrasting them, and highlight appropriate clinical situations in which they might be used. We also discuss the future of chemotherapy for melanoma, noting the potential for combinations of chemotherapy with either targeted or immunotherapeutic agents.
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Affiliation(s)
- Jason J Luke
- Department of Medicine, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Umemura A, Nitta H, Sasaki A, Takahara T, Hasegawa Y, Wakabayashi G. Pure laparoscopic posterior sectionectomy for liver metastasis resulting from choroidal malignant melanoma: a case report. Asian J Endosc Surg 2013; 6:318-21. [PMID: 24308594 DOI: 10.1111/ases.12043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 04/25/2013] [Accepted: 05/07/2013] [Indexed: 12/14/2022]
Abstract
Liver metastases resulting from primary choroidal malignant melanomas occur frequently and have a poor prognosis. As a result of advancements in multidisciplinary approaches, life expectancy can be increased when R0 resection is possible. Herein we report the surgical outcomes of pure laparoscopic posterior sectionectomy (PLPS) in a patient with a solitary liver metastasis resulting from choroidal malignant melanoma. The subject was a 46-year-old Japanese man who had received radiotherapy for primary right choroidal malignant melanoma 2 years before presenting at our hospital; he subsequently underwent ophthalmectomy as a result of the relapse. During follow-up, CT revealed a metastatic lesion in the liver S7, and interventional treatments were performed sequentially. The lesion still showed a tendency to enlarge, so we performed PLPS. On postoperative day 7, the patient was discharged from the hospital, and he started to receive adjuvant chemotherapy 2 weeks after PLPS. Although PLPS is deemed to be difficult for lesions in the upper part or posterior segment of the liver, we performed this modality safely.
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Affiliation(s)
- Akira Umemura
- Department of Surgery, Iwate Medical University, Morioka, Japan
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12
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Recent advances and developments in the antitumor effect of the HVJ envelope vector on malignant melanoma: from the bench to clinical application. Cancer Gene Ther 2013; 20:599-605. [PMID: 24157924 DOI: 10.1038/cgt.2013.61] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 08/23/2013] [Accepted: 09/17/2013] [Indexed: 12/31/2022]
Abstract
Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) are considered to be safe and efficient non-viral vectors used for drug delivery, since they can incorporate DNA, RNA, proteins and drugs. We have recently found that HVJ-E has a novel antitumor immune effect using a colon cancer model. HVJ-E has also been shown to have both direct and immune-mediated indirect actions against malignancy. Intratumoral injection of an inactivated HVJ-E solution significantly reduced the tumor volume and prevented spontaneous lung metastasis, leading to an increased overall survival in C57/BL6 mice transplanted with B16/BL6 mouse melanoma cells, and even in immunodeficient mice transplanted with Mewo human melanoma cells. No severe adverse effects including laboratory data abnormalities or anaphylactic reactions were observed. The comprehensive mechanism(s) underlying the immunological effects of HVJ-E appear to include not only enhanced effector T cell- and/or natural killer (NK) cell-mediated immunity, but also rescue from regulatory T cell (Treg)-mediated immunosuppression, presumably through the interleukin-6 secretion from dendritic cells stimulated by HVJ-E. Since a protocol for a clinical study of HVJ-E in malignant melanoma was approved in 2009 by the ethics committee of Osaka University and of the Medical Center for Translational Research in Osaka University Hospital, a phase I/IIa study for advanced malignant melanoma patients was just started. In this review, we show several favorable results regarding the antitumor effects of HVJ-E and describe the novel mechanism underlying this tumor immune response. Since we are conducting a phase I/IIa clinical trial using HVJ-E in advanced melanoma patients on the basis of preclinical results, detailed clinical information and immune-monitoring data are also introduced. The development of new therapeutic modalities for advanced melanoma patients is urgently needed, and we hope that HVJ-E may provide one such treatment.
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El-Khattouti A, Selimovic D, Haïkel Y, Megahed M, Gomez CR, Hassan M. Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response. Cancer Lett 2013; 343:123-33. [PMID: 24080340 DOI: 10.1016/j.canlet.2013.09.024] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 09/19/2013] [Accepted: 09/20/2013] [Indexed: 02/07/2023]
Abstract
The presence and the involvement of cancer stem-like cells (CSCs) in tumor initiation and progression, and chemo-resistance are documented. Herein, we functionally analyzed melanoma stem-like cells (MSC)/CD133(+) cells on their resistance and response to taxol-induced apoptosis. Besides being taxol resistant, the CD133(+) cells demonstrated a growth advantage over the CD133(-) subpopulation. Taxol induced apoptosis on CD133(-) cells, but not on CD133(+) cells. In the CD133(-) subpopulation, the exposure to taxol induced the activation of apoptosis signal-regulating kinase1 (ASK1)/c-jun-N-terminal kinase (JNK), p38, extracellular signal regulated kinase (ERK) pathways and Bax expression, while in CD133(+) cells taxol was able only to enhance the activity of the ERK pathway. In CD133(+) cells, the direct gene transfer of Bax overcame the acquired resistance to taxol. Taken together, our data provide an insight into the mechanistic cascade of melanoma resistance to taxol and suggest Bax gene transfer as a complementary approach to chemotherapy.
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Affiliation(s)
| | - Denis Selimovic
- Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
| | - Youssef Haïkel
- Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
| | - Mosaad Megahed
- Clinic of Dermatology, University Hospital of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Christian R Gomez
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Mohamed Hassan
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA; Institut National de la Santé et de la Recherche Médicale, U 977, University of Strasbourg, 67000 Strasbourg, France; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France.
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14
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Myeloprotection by cytidine deaminase gene transfer in antileukemic therapy. Neoplasia 2013; 15:239-48. [PMID: 23479503 DOI: 10.1593/neo.121954] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 01/03/2013] [Accepted: 01/07/2013] [Indexed: 12/22/2022] Open
Abstract
Gene transfer of drug resistance (CTX-R) genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has been proven by overexpression of a mutant O(6)-methylguaninemethyltransferase in the hematopoietic system of glioblastoma patients treated with temozolomide. Given its protection capacity against such relevant drugs as cytosine arabinoside (ara-C), gemcitabine, decitabine, or azacytidine and the highly hematopoiesis-specific toxicity profile of several of these agents, cytidine deaminase (CDD) represents another interesting candidate CTX-R gene and our group recently has established the myeloprotective capacity of CDD gene transfer in a number of murine transplant studies. Clinically, CDD overexpression appears particularly suited to optimize treatment strategies for acute leukemias and myelodysplasias given the efficacy of ara-C (and to a lesser degree decitabine and azacytidine) in these disease entities. This article will review the current state of the art with regard to CDD gene transfer and point out potential scenarios for a clinical application of this strategy. In addition, risks and potential side effects associated with this approach as well as strategies to overcome these problems will be highlighted.
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Ryu SW, Saw R, Scolyer RA, Crawford M, Thompson JF, Sandroussi C. Liver resection for metastatic melanoma: equivalent survival for cutaneous and ocular primaries. J Surg Oncol 2013; 108:129-35. [PMID: 23813600 DOI: 10.1002/jso.23361] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 05/20/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND The value of surgical resection in patients with hepatic metastases from melanoma is poorly documented in the literature. This study sought to determine the clinicopathologic and surgical factors predictive of outcome for melanoma patients who underwent resection of hepatic metastases. METHODS Thirty-three patients who underwent liver resection for melanoma metastases were identified from the Melanoma Institute Australia research database. Univariate and multivariate analyses were performed to identity factors predictive of recurrence and survival following liver resection for melanoma metastasis. RESULTS The actuarial 2- and 5-year survival rates were 59% and 42%, respectively, with a median survival of 29 months (range 1-139). The 5-year survival rates for cutaneous and ocular primary melanoma were 44% and 39%, respectively. Improved post-hepatic metastasectomy survival was observed in patients with microscopically clear resection margins (R0, 44 months; R1/2, 12 months; P = 0.04). Although major hepatic resection was associated with improved survival (major, 70 months; minor, 23 months; P = 0.07), major hepatectomies were performed almost exclusively in patients with isolated liver metastases. CONCLUSIONS Hepatic resection for metastatic melanoma is associated with improved survival in selected patients with both primary ocular and cutaneous melanoma. Surgical treatment of hepatic melanoma metastases should be considered when complete resection is feasible.
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Affiliation(s)
- Seung Wook Ryu
- Department of Hepatobiliary and Upper Gastrointestinal Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia
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16
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XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts. Anticancer Drugs 2013; 24:181-8. [PMID: 23059386 DOI: 10.1097/cad.0b013e32835a43f1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Mebendazole (MBZ) was identified as a promising therapeutic on the basis of its ability to induce apoptosis in melanoma cell lines through a B-cell lymphoma 2 (BCL2)-dependent mechanism. We now show that in a human xenograft melanoma model, oral MBZ is as effective as the current standard of care temozolomide in reducing tumor growth. Inhibition of melanoma growth in vivo is accompanied by phosphorylation of BCL2 and decreased levels of X-linked inhibitor of apoptosis (XIAP). Reduced expression of XIAP on treatment with MBZ is partially mediated by its proteasomal degradation. Furthermore, exposure of melanoma cells to MBZ promotes the interaction of SMAC/DIABLO with XIAP, thereby alleviating XIAP's inhibition on apoptosis. XIAP expression on exposure to MBZ is indicative of sensitivity to MBZ as MBZ-resistant cells do not show reduced levels of XIAP after treatment. Resistance to MBZ can be reversed partially by siRNA knockdown of cellular levels of XIAP. Our data indicate that MBZ is a promising antimelanoma agent on the basis of its effects on key antiapoptotic proteins.
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Sin JI, Kim H, Ahn E, Jeon YH, Park WS, Lee SY, Kwon B. Combined stimulation of TLR9 and 4.1BB augments Trp2 peptide vaccine-mediated melanoma rejection by increasing Ag-specific CTL activity and infiltration into tumor sites. Cancer Lett 2012; 330:190-9. [PMID: 23219755 DOI: 10.1016/j.canlet.2012.11.045] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 10/17/2012] [Accepted: 11/27/2012] [Indexed: 01/08/2023]
Abstract
Peptide vaccines are a clinically applicable therapy shown to be effective in tumor control. In this study, Trp2 peptides plus CpG-oligodeoxynucleotide treatment was found to induce Ag-specific IFN-γ and CD8+CTL responses, and antitumor activity against large established melanoma (tumor size, 7mm). A combination of anti-4.1BB antibodies with Trp2 peptides+CpG-oligodeoxynucleotide increased the antitumor cure rate from 0% to 75%. This effect was concomitant with greater induction of Ag-specific CD8+CTLs and their infiltration into the tumor sites, highlighting the importance of combined stimulation of TLR9 and 4.1BB for achieving tumor eradication. These findings may have implications for designing peptide-based therapeutic vaccines for cancer-patients.
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Affiliation(s)
- Jeong-Im Sin
- Department of Microbiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea.
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18
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Du SD, Mao YL, Li SH, Sang XT, Lu X, Xu YY, Xu HF, Zhao L, Bai CM, Zhong SX, Huang JF. Surgical resection plus biotherapy/chemotherapy improves survival of hepatic metastatic melanoma. World J Hepatol 2012; 4:305-10. [PMID: 23293716 PMCID: PMC3536837 DOI: 10.4254/wjh.v4.i11.305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 10/12/2012] [Accepted: 11/02/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the correlation of treatment method with the outcome of all the hepatic metastatic melanoma (HMM) patients from our hospital. METHODS There were altogether nine cases of HMM that had been treated in the PUMCH hospital during the past 25 years, from December 1984 to February 2010. All of the cases developed hepatic metastasis from primary cutaneous melanoma. A retrospective review was performed on all the cases in order to draw informative conclusion on diagnosis and treatment in correlation with the prognosis. Clinical features including symptoms, signs, blood test results, B-ultrasound and computed tomography (CT) imaging characteristics, and pathological data were analyzed in each case individually. A simple comparison was made on case by case basis instead of performing statistical analysis since the case numbers are low and patients were much diversified in each item that has been analyzed. Literatures on this subject were reviewed in order to draw a safe conclusion and found to be supportive to our finding in a much broad scope. RESULTS There are six males and three females whose ages ranged 39-74 years old with an average of 58.8. Patients were either with or without symptoms at the time of diagnosis. The liver function and tumor marker exam were normal in all but one patient. The incidence of HMM does not affect liver function and was not related to virus infection status in the liver. Most of these HMM patients were also accompanied by the metastases of other locations, including lung, abdominal cavity, and cervical lymph nodes. Ultrasound examinations showed lesions ranging 2-12 cm in diameter, with no- or low-echo peripheral areola. Doppler showed blood flow appeared inside some tumors as well as in the surrounding area. CT image demonstrated low density without uniformed lesions, characterized with calcification in periphery, and enhanced in the arterial phase. Contrast phase showed heterogeneous enhancement, with a density higher than normal liver tissue, which was especially apparent at the edge. Patients were treated differently with following procedures: patients #1, #6 and #8 were operated with hepatectomy with or without removal of primary lesion, and followed by comprehensive biotherapy/chemotherapy; patient #9 received hepatectomy only; patient #2 received bacille calmette-guerin treatment only; patient #7 had Mile's surgery but no hepatectomy; and patients #3, #4 and #5 had supportive treatment without specific measurement. The patients who had resections of metastatic lesions followed by post-operative comprehensive therapy have an average survival time of 30.7 mo, which is much longer than those did not receive surgery treatment (4.6 mo). Even for the patient receiving a resection of HMM only, the post-operative survival time was 18 mo at the time we reviewed the data. This patient and the patient #6 are still alive currently and subjected to continue following up. CONCLUSION Surgical operation should be first choice for HMM treatment, and together with biotherapy/chemotherapy, hepatectomy is likely to bring better prognosis.
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Affiliation(s)
- Shun-Da Du
- Shun-Da Du, Yi-Lei Mao, Shao-Hua Li, Xin-Ting Sang, Xin Lu, Yi-Yao Xu, Hai-Feng Xu, Shou-Xian Zhong, Jie-Fu Huang, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Kim H, Sin JI. Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism. Hum Vaccin Immunother 2012; 8:1714-21. [PMID: 23151450 DOI: 10.4161/hv.22346] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.
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Affiliation(s)
- Ha Kim
- Department of Microbiology, School of Medicine, Kangwon National University; Chuncheon, Gangwon-do, Korea
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20
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Alvarez-Downing MM, Inchauste SM, Dudley ME, White DE, Wunderlich JR, Rosenberg SA, Kammula US. Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma. World J Surg Oncol 2012; 10:113. [PMID: 22726267 PMCID: PMC3408344 DOI: 10.1186/1477-7819-10-113] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 06/22/2012] [Indexed: 12/18/2022] Open
Abstract
Background Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. Methods A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. Results Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months). Conclusions Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.
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Affiliation(s)
- Melissa M Alvarez-Downing
- Surgery Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Building 10 Hatfield CRC, Room 3-5930, Bethesda, MD 20892-1201, USA
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Selimovic D, Sprenger A, Hannig M, Haïkel Y, Hassan M. Apoptosis related protein-1 triggers melanoma cell death via interaction with the juxtamembrane region of p75 neurotrophin receptor. J Cell Mol Med 2012; 16:349-61. [PMID: 21418516 PMCID: PMC3823298 DOI: 10.1111/j.1582-4934.2011.01304.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 03/15/2011] [Indexed: 12/03/2022] Open
Abstract
Although chemotherapeutic drugs could theoretically target all metastatic sites, current treatments do not provide complementary therapeutics. Therefore, the development of an alternative approach replacing the traditional therapy is urgently needed. To assess the killing efficiency of the functionally identified apoptosis-related protein (APR)-1 in melanoma cells, we established a system for the regulated expression of APR-1. The induction of APR-1 expression caused apoptosis of melanoma cells via the interaction with the juxtamembrane region of p75 neurotrophin receptor (p75NTR), and possible also via the competition with tumour necrosis factor receptor-associated factor-6 (TRAF6) and the catalytic receptor of neurotrophin (Trk) for the same p75NTR interacting site. The accumulation of APR-1 in melanoma cells may block the physical association of p75NRT with TRAF6 and/or Trk, leading to the disruption of both NF-κB and extracellular signal-regulated kinase (ERK) pathways. Also, accumulation of APR-1 protein enhanced the activity of both c-Jun-N-terminal kinase (JNK) and p38 pathways. However, the analysis of APR-1-modulated pathways demonstrated the involvement of apoptosis-regulating kinase 1-JNK/p38 pathway in the induction of Bax expression leading to both mitochondrial dysregulation [as demonstrated by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis-inducing factor into cytoplasm, and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP)] and endoplasmic reticulum stress as demonstrated by the increase of intracellular Ca(2+) release. Thus, besides the analysis of its pro-apoptotic function, our data provide insight into the molecular mechanism of APR-1-induced apoptosis of melanoma cells.
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Affiliation(s)
- Denis Selimovic
- Institut National de la Santé et de la Recherche Médicale (INSERM U977), University of StrasbourgStrasbourg, France
- Department of Oral Medicine and Surgery, Dental Faculty, University of StrasbourgStrasbourg, France
| | - Achim Sprenger
- Laboratory for Molecular Tumour Therapy, Clinic of Dermatology, University Hospital of DuesseldorfDuesseldorf, Germany
| | - Matthias Hannig
- Department of Operative Dentistry and Preventive Dentistry, Saarland UniversityHomburg/Saar, Germany
| | - Youssef Haïkel
- Institut National de la Santé et de la Recherche Médicale (INSERM U977), University of StrasbourgStrasbourg, France
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of StrasbourgStrasbourg, France
| | - Mohamed Hassan
- Institut National de la Santé et de la Recherche Médicale (INSERM U977), University of StrasbourgStrasbourg, France
- Laboratory for Molecular Tumour Therapy, Clinic of Dermatology, University Hospital of DuesseldorfDuesseldorf, Germany
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of StrasbourgStrasbourg, France
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Linos K, Slominski A, Ross JS, Carlson JA. Melanoma update: diagnostic and prognostic factors that can effectively shape and personalize management. Biomark Med 2011; 5:333-60. [PMID: 21657842 DOI: 10.2217/bmm.11.39] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Routine light microscopy remains a powerful tool to diagnose, stage and prognose melanoma. Although it is very economical and efficient, it requires a significant level of expertise and, in difficult cases the final diagnosis is affected by subjective interpretation. Fortunately, new insights into the genomic aberrations characteristic of melanoma, coupled with ancillary studies, are further refining evaluation and management allowing for more confident diagnosis, more accurate staging and the selection of targeted therapy. In this article, we review the standard of care and new updates including four probe FISH, the 2009 American Joint Commission on Cancer staging of melanoma and mutant testing of melanoma, which will be crucial for targeted therapy of metastatic melanoma.
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Caralt M, Martí J, Cortés J, Fondevila C, Bilbao I, Fuster J, García-Valdecasas JC, Sapisochín G, Balsells J, Charco R. Outcome of patients following hepatic resection for metastatic cutaneous and ocular melanoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:268-75. [PMID: 21057964 DOI: 10.1007/s00534-010-0341-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE The aim of this study was to analyze the outcome of patients undergoing hepatic resection for melanoma liver metastases. METHODS Patients undergoing liver resection for melanoma metastases at the Hospital Vall d'Hebron and Hospital Clinic, Barcelona, were reviewed. Selection criteria were: good performance status, feasibly complete and safe resection, and absence of visceral extrahepatic metastases. RESULTS Between 1994 and 2007, 14 liver resections were performed for melanoma liver metastases. The primary tumor was cutaneous in 8 patients and ocular in 6. Two patients underwent urgent liver surgery due to tumor bleeding. In these patients, complete melanoma staging was not performed and extrahepatic metastases were found during surgery or during the postoperative course. Six of 13 patients (46.2%) developed liver recurrence during follow-up. One- and 3-year actuarial patient survivals were 77 and 49%, respectively. Excluding the patients who underwent urgent liver surgery, the 1- and 3-year actuarial patient survivals in those with primary ocular and cutaneous melanoma were 83 and 56% and 80 and 60%, respectively. CONCLUSIONS Liver resection may be considered as part of oncosurgical treatment in patients with melanoma liver metastases, since prolonged survival was observed, albeit with a high recurrence rate. Nevertheless, it should be taken into account that our study included only a small number of patients.
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Affiliation(s)
- Mireia Caralt
- Department of HepatoBilioPancreatic Surgery and Transplants, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
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Selimovic D, Ahmad M, El-Khattouti A, Hannig M, Haïkel Y, Hassan M. Apoptosis-related protein-2 triggers melanoma cell death by a mechanism including both endoplasmic reticulum stress and mitochondrial dysregulation. Carcinogenesis 2011; 32:1268-78. [PMID: 21693538 DOI: 10.1093/carcin/bgr112] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Metastatic cancers including melanoma are frequently associated with increased resistance to apoptosis induced by various therapeutic modalities, and the success of systemic therapy for the treatment of metastatic melanoma is minimal. In the present study, we demonstrated the ability of apoptosis-related protein (APR)-2 to trigger cell death via mechanism mediated by both endoplasmic reticulum (ER) stress [as evidenced by the increase of intracellular Ca(2+) release, the activation of both, inositol-requiring enzyme 1α (IRE1α) and calpain and cleavage of caspase-4] and mitochondrial dysregulation as evidenced by the loss of mitochondrial membrane potential, Cytochrome c release and cleavage of caspases-9 and -3, and poly adenosine diphosphate ribose polymerase (PARP). Also, the activation of apoptosis signal-regulating kinase (ASK) 1, c-jun-N-terminal kinase (JNK) and the transcription factors AP-1 and p53, and the induction of Bax expression were noted in APR-2-expressing cells. Both immune fluorescence staining and western blotting revealed the localization of APR-2 at ER and Bax protein at both mitochondria and ER. However, data of inhibitory experiments demonstrated that APR-2-induced apoptosis of melanoma cells is mediated by three parallel pathways: one of them IRE1/tumour necrosis factor receptor-associated factor 2/ASK1/JNK/Cyt.c/caspase-9/caspase-3/PARP) seems to be mitochondrial dependent, whereas, the other two pathways namely calpain/caspase-4/caspase-9/caspase-3/PARP and protein kinase RNA-like ER kinase/ATF4/C/EBP homologous protein (CHOP)/Bim seem to be mitochondrial independent. In conclusion, our data provide insight into the molecular mechanism of APR-2-induced apoptosis and suggest APR-2 gene transfer as an alternative approach for the treatment of chemoresistance melanoma metastasis.
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Affiliation(s)
- Denis Selimovic
- INSERM U977, and Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, Strasbourg, France
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Cytoplasmic Skp2 expression is increased in human melanoma and correlated with patient survival. PLoS One 2011; 6:e17578. [PMID: 21386910 PMCID: PMC3046256 DOI: 10.1371/journal.pone.0017578] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 02/09/2011] [Indexed: 12/05/2022] Open
Abstract
Background S-phase kinase protein 2 (Skp2), an F-box protein, targets cell cycle regulators via ubiquitin-mediated degradation. Skp2 is frequently overexpressed in a variety of cancers and associated with patient survival. In melanoma, however, the prognostic significance of subcellular Skp2 expression remains controversial. Methods To investigate the role of Skp2 in melanoma development, we constructed tissue microarrays and examined Skp2 expression in melanocytic lesions at different stages, including 30 normal nevi, 61 dysplastic nevi, 290 primary melanomas and 146 metastatic melanomas. The TMA was assessed for cytoplasmic and nuclear Skp2 expression by immunohistochemistry. The Kaplan-Meier method was used to evaluate the patient survival. The univariate and multivariate Cox regression models were performed to estimate the harzard ratios (HR) at five-year follow-up. Results Cytoplasmic but not nuclear Skp2 expression was gradually increased from normal nevi, dysplastic nevi, primary melanomas to metastatic melanomas. Cytoplasmic Skp2 expression correlated with AJCC stages (I vs II–IV, P<0.001), tumor thickness (≤2.00 vs >2.00 mm, P<0.001) and ulceration (P = 0.005). Increased cytoplasmic Skp2 expression was associated with a poor five-year disease-specific survival of patients with primary melanoma (P = 0.018) but not metastatic melanoma (P>0.05). Conclusion This study demonstrates that cytoplasmic Skp2 plays an important role in melanoma pathogenesis and its expression correlates with patient survival. Our data indicate that cytoplasmic Skp2 may serve as a potential biomarker for melanoma progression and a therapeutic target for this disease.
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Jiang G, Wei ZP, Pei DS, Xin Y, Liu YQ, Zheng JN. A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy. Biochem Biophys Res Commun 2011; 406:311-4. [PMID: 21329652 DOI: 10.1016/j.bbrc.2011.02.042] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 02/11/2011] [Indexed: 12/21/2022]
Abstract
Malignant glioma is the most common primary brain tumor. Malignant melanoma is the most malignant of skin tumor. The two malignancies are poorly responsive to conventional treatment regimens such as chemotherapy. Temozolomide (TMZ) is a DNA-alkylating agent used for the treatment of glioma, astrocytoma, and melanoma. Resistance to alkylating agents such as TMZ correlates with increased expression of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Several studies in animal models have demonstrated that decreasing MGMT level with gene therapy could overcome TMZ resistance and enhance tumor cell death. In the present review, we provide an overview of recent advances in this field.
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Affiliation(s)
- Guan Jiang
- Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China
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Klapper JA, Davis JL, Ripley RT, Smith FO, Nguyen DM, Kwong KF, Mercedes L, Kemp CD, Mathur A, White DE, Dudley ME, Wunderlich JR, Rosenberg SA, Schrump DS. Thoracic metastasectomy for adoptive immunotherapy of melanoma: a single-institution experience. J Thorac Cardiovasc Surg 2010; 140:1276-82. [PMID: 20584535 PMCID: PMC7241866 DOI: 10.1016/j.jtcvs.2010.05.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Revised: 04/23/2010] [Accepted: 05/16/2010] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Although refractory to chemotherapy, metastatic melanoma may respond to adoptive immunotherapy. As novel treatments evolve, surgeons may be asked to perform metastasectomy not only for palliation or potential cure but also for isolation of tumor-infiltrating lymphocytes. This study was undertaken to examine outcomes of patients with melanoma undergoing thoracic metastasectomy in preparation for investigational immunotherapy. METHODS A retrospective review identified 107 consecutive patients who underwent 116 thoracic metastasectomy procedures from April 1998 to July 2009. Indications for surgical intervention included procurement of tumor-infiltrating lymphocytes, rendering of patients to no evaluable disease status, palliation, and diagnosis. Response Evaluation Criteria in Solid Tumors criteria were used to assess tumor response. RESULTS Thoracotomy, lobectomy, and video-assisted thoracoscopic surgery with nonanatomic resection were the most common procedures. Major complications included 1 death and 1 coagulopathy-induced hemothorax. Seventeen patients were rendered to no evaluable disease status. Virtually all patients with residual disease had tumor specimens cultured for tumor-infiltrating lymphocytes; approximately 70% of tumor-infiltrating lymphocyte cultures exhibited antitumor reactivity. Of the 91 patients with residual or recurrent disease, 24 (26%) underwent adoptive cell transfer of tumor-infiltrating lymphocytes, of whom 7 exhibited objective responses (29% response rate and 8% based on intent to treat). Rapid disease progression precluded tumor-infiltrating lymphocyte therapy in most cases. Actuarial 1- and 5-year survival rates for patients rendered to no evaluable disease status or receiving or not receiving tumor-infiltrating lymphocytes were 93% and 76%, 64% and 33%, and 43% and 0%, respectively. CONCLUSIONS Relatively few patients currently having thoracic metastasectomy undergo adoptive cell transfer. Continued refinement of tumor-infiltrating lymphocyte expansion protocols and improved patient selection might increase the number of patients with melanoma benefiting from these interventions.
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Affiliation(s)
- Jacob A. Klapper
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jeremy L. Davis
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - R. Taylor Ripley
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Franz O. Smith
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Dao M. Nguyen
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - King F. Kwong
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Leandro Mercedes
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Clinton D. Kemp
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Aarti Mathur
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Donald E. White
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Mark E. Dudley
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - John R. Wunderlich
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Steven A. Rosenberg
- Tumor Immunology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - David S. Schrump
- Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Abstract
Paraneoplastic syndromes are an uncommon, yet well-described, phenomenon in cancer patients. The syndrome of granulocytosis caused by granulocyte colony-stimulating factor (G-CSF) production by tumors is rare and is difficult to diagnose in patients receiving treatment for metastatic disease. From January 2005 to May 2009, 626 patients were evaluated for treatment of metastatic melanoma. At initial evaluation or during the course of treatment, six patients had an elevated white blood cell count and no evidence of infection. All six had significantly elevated serum G-CSF. The level of serum G-CSF was directly correlated with the absolute neutrophil count. In-vitro assay of melanoma tumor from two patients showed elevated G-CSF in cell culture supernatant. The paraneoplastic syndrome of granulocytosis resulting from ectopic G-CSF production in patients with metastatic melanoma is rare. This diagnosis should be considered when common causes of granulocytosis have been ruled out.
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Affiliation(s)
- Jeremy L. Davis
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - R. Taylor Ripley
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Timothy L. Frankel
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Irina Maric
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Jay N. Lozier
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Steven A. Rosenberg
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, Villegas-Portero R, Nieto-Garcia A. Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety. Oncologist 2010; 15:416-27. [PMID: 20348274 DOI: 10.1634/theoncologist.2009-0325] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits. METHODS A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used. RESULTS Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively. CONCLUSIONS ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.
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Affiliation(s)
- David Moreno-Ramirez
- Melanoma Unit, Dermatology Department, Hospital Universitario Virgen Macarena, Seville, Spain.
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Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer 2010; 116:155-63. [PMID: 19877111 DOI: 10.1002/cncr.24720] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND nab-Paclitaxel (ABI-007, Abraxane), a 130-nM, albumin-bound (nab) particle form of Cremophor-free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab-paclitaxel were evaluated in previously treated and chemotherapy-naive patients with metastatic melanoma (MM). METHODS Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab-Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m(2) (in previously treated patients) or 150 mg/m(2) (in chemotherapy-naive patients). RESULTS Thirty-seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy-naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy-naive cohorts, respectively. The median progression-free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy-naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy-naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy-naive patients were treated without dose reduction. Eight (22%) chemotherapy-naive patients discontinued therapy because of toxicities. Drug-related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue. CONCLUSIONS nab-Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy-naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab-Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. (c) 2010 American Cancer Society.
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Affiliation(s)
- Evan M Hersh
- Department of Medicine, Arizona Cancer Center, Tucson, AZ 85724, USA.
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31
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32
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Study and Treatment of Locally Advanced Melanoma. ACTAS DERMO-SIFILIOGRAFICAS 2009. [DOI: 10.1016/s1578-2190(09)70172-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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33
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Ripley RT, Davis JL, Klapper JA, Mathur A, Kammula U, Royal RE, Yang JC, Sherry RM, Hughes MS, Libutti SK, White DE, Steinberg SM, Dudley ME, Rosenberg SA, Avital I. Liver resection for metastatic melanoma with postoperative tumor-infiltrating lymphocyte therapy. Ann Surg Oncol 2009; 17:163-70. [PMID: 19777192 DOI: 10.1245/s10434-009-0677-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2009] [Revised: 07/28/2009] [Accepted: 07/29/2009] [Indexed: 01/28/2023]
Abstract
BACKGROUND Patients with metastatic melanoma to the liver (MML) have a median survival of 4 to 6 months. This study evaluated patients who underwent liver resection with intent to receive postoperative tumor-infiltrating lymphocyte (TIL) therapy. METHODS Retrospective analysis of a prospective database identified patients with MML who underwent liver resection from 1980 to 2008. RESULTS A total of 539 patients had MML, and 39% (204 of 539) had tumor collected for TIL. A total of 17% (35 of 204) underwent liver resection for TIL. The 3-year overall survival was 53%. Lack of extrahepatic disease (P = .026), negative margin (P = .056), and single hepatic metastasis (P = .04) predicted survival after univariate analysis. Only lack of extrahepatic disease remained a significant predictor of survival after multivariate analysis (P = .043). A total of 31% (11 of 35) underwent complete resection without TIL, and 69% (24 of 35) underwent resection with synchronous intrahepatic and extrahepatic disease with intent to receive TIL. For 9 of 11 patients (2 of 11 excluded for gene therapy), 3-year survival was 80%. A total of 4 (44%) of 9 experienced recurrence, with a median disease-free survival of 1.2 years. For 24 patients (69%) with residual disease, 3-year survival was 51% (2 of 24 excluded for gene therapy). A total of 63% (15 of 24) received postoperative TIL (3-year survival 65%), and 29% (7 of 24) did not. A total of 40% (6 of 15) had disease that partially responded to TIL; the disease of 67% (4 of 6) had not progressed at median follow-up of 55 months (range, 42-197+ months). The seven patients who did not receive TIL had a median survival of 4.6 months. CONCLUSIONS Resection of MML with TIL should be considered because it can result in prolonged survival in a highly selected group of patients.
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Affiliation(s)
- R Taylor Ripley
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Wu Y, Jiang P, Lin Y, Chen S, Lin N, Li J. Expression of phosphorylated-STAT3 and osteopontin and their correlation in melanoma. ACTA ACUST UNITED AC 2009; 29:246-50. [DOI: 10.1007/s11596-009-0223-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Indexed: 01/02/2023]
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Naumann SC, Roos WP, Jöst E, Belohlavek C, Lennerz V, Schmidt CW, Christmann M, Kaina B. Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. Br J Cancer 2009; 100:322-33. [PMID: 19127257 PMCID: PMC2634706 DOI: 10.1038/sj.bjc.6604856] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O6-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg−1 protein, and there was a correlation between MGMT activity and the level of resistance to TMZ and fotemustine. MGMT inactivation by O6-benzylguanine sensitized all melanoma cell lines expressing MGMT to TMZ and fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O6-alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to TMZ without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and TMZ sensitivity was not found. Apoptosis in melanoma cells induced by TMZ and fotemustine was accompanied by double-strand break (DSB) formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For TMZ, DSBs correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to TMZ and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with TMZ. Overall, the findings are in line with the model that in melanoma cells TMZ-induced O6-methylguanine triggers the apoptotic (and necrotic) pathway through DSBs, whereas for chloroethylating agents apoptosis is triggered in a more complex manner.
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Affiliation(s)
- S C Naumann
- Department of Toxicology, University of Mainz, Mainz, Germany
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36
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Carlson JA, Ross JS, Slominski AJ. New techniques in dermatopathology that help to diagnose and prognosticate melanoma. Clin Dermatol 2009; 27:75-102. [DOI: 10.1016/j.clindermatol.2008.09.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Doudican N, Rodriguez A, Osman I, Orlow SJ. Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res 2008; 6:1308-15. [PMID: 18667591 DOI: 10.1158/1541-7786.mcr-07-2159] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 micromol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC(50) of 0.32 micromol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent.
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Affiliation(s)
- Nicole Doudican
- New York University School of Medicine, New York, NY 10016, USA
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38
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Abstract
This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.
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Affiliation(s)
- Marko Lens
- King's College, Genetic Epidemiology Unit, St Thomas's Hospital, London
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39
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Dai DL, Wang Y, Liu M, Martinka M, Li G. Bim Expression Is Reduced in Human Cutaneous Melanomas. J Invest Dermatol 2008; 128:403-7. [PMID: 17637819 DOI: 10.1038/sj.jid.5700989] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Bim is a BH3-only protein belonging to the Bcl-2 family of apoptotic regulators. Upon activation, Bim can antagonize all the prosurvival Bcl-2 proteins, leading to apoptosis. To investigate whether Bim plays a role in melanoma progression, we used tissue microarray and immunohistochemistry to measure Bim expression in 52 cases of dysplastic nevi, 159 cases of primary melanomas and 52 cases of melanoma metastases, and evaluated the prognostic value of Bim expression. Our results showed that Bim expression is reduced as melanoma progresses. Significant differences for Bim staining pattern were observed between dysplastic nevi and metastatic melanomas (P<0.001, chi2 test), and between primary melanomas and metastatic melanomas (P<0.001, chi2 test). Moreover, reduced Bim expression is significantly correlated with poor 5-year survival of melanoma patients but failed to be an independent prognostic factor by Cox regression analysis. Our data suggest that Bim loss may play an important role in melanoma progression.
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Affiliation(s)
- Derek L Dai
- Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver, British Columbia, Canada
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Abstract
Cancer stem cells (CSC) have been identified in hematological malignancies and several solid cancers. Similar to physiological stem cells, CSC are capable of self-renewal and differentiation and have the potential for indefinite proliferation, a function through which they may cause tumor growth. Although conventional anti-cancer treatments might eradicate most malignant cells in a tumor, they are potentially ineffective against chemoresistant CSC, which may ultimately be responsible for recurrence and progression. Human malignant melanoma is a highly aggressive and drug-resistant cancer. Detection of tumor heterogeneity, undifferentiated molecular signatures, and increased tumorigenicity of melanoma subsets with embryonic-like differentiation plasticity strongly suggest the presence and involvement of malignant melanoma stem cells (MMSC) in the initiation and propagation of this malignancy. Here, we review these findings in the context of functional properties ascribed to melanocyte stem cells and CSC in other cancers. We discuss the association of deregulated signaling pathways, genomic instability, and vasculogenic mimicry phenomena observed in melanoma subpopulations in light of the CSC concept. We propose that a subset of MMSC may be responsible for melanoma therapy-resistance, tumor invasiveness, and neoplastic progression and that targeted abrogation of a MMSC compartment could therefore ultimately lead to stable remissions and perhaps cures of metastatic melanoma.
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Affiliation(s)
- Tobias Schatton
- Transplantation Research Center, Children’s Hospital Boston & Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Markus H Frank
- Transplantation Research Center, Children’s Hospital Boston & Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Majer M, Jensen RL, Shrieve DC, Watson GA, Wang M, Leachman SA, Boucher KM, Samlowski WE. Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases. Cancer 2007; 110:1329-37. [PMID: 17623835 DOI: 10.1002/cncr.22905] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment. METHODS Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery >or=28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-alpha-2B. The primary endpoint was survival from the time of the initial diagnosis of metastatic disease. RESULTS Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months. CONCLUSIONS Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present.
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Affiliation(s)
- Martin Majer
- Multidisciplinary Melanoma Program, Huntsman Cancer Institute, Salt Lake City, Utah, USA
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42
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Tas F, Camlica H, Topuz E. Temozolomide in combination with fotemustine in patients with metastatic melanoma. Cancer Chemother Pharmacol 2007; 62:293-8. [PMID: 17909803 DOI: 10.1007/s00280-007-0606-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2007] [Accepted: 09/14/2007] [Indexed: 11/29/2022]
Abstract
PURPOSE Temozolomide and fotemustine are both active drugs for treating metastatic melanoma. The present study was designed to assess the efficacy and safety of combination therapy with temozolomide + fotemustine in patients with metastatic melanoma. METHODS Forty patients (median age 50.5 and 22 males) with pathologically confirmed, unresectable, AJCO stage IV melanoma were enrolled into the study. The primary endpoints were tumor response and safety. Patients received oral temozolomide 125 mg/m(2) on days 1-7 and intravenous fotemustine 80 mg/m(2) on day 3 every 3 weeks. RESULTS Fourteen (35%) patients achieved an objective response, including 3 (7.5%) complete and 11 (27.5%) partial responses. Median overall survival time was 6.7 months and 6-month survival rate was 57.4%. Myelosupression, particularly thrombocytopenia, was the primary toxicity. CONCLUSION The regimen, temozolomide combined with fotemustine, is an active and moderately safe first-line chemotherapy regimen with acceptable and easily manageable toxicities in patients with metastatic melanoma.
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Affiliation(s)
- Faruk Tas
- Institute of Oncology, Istanbul University, Capa, 34390, Istanbul, Turkey.
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43
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Tyre CC, Quan W. Nursing Care of Patients Receiving High-Dose, Continuous-Infusion Interleukin-2 With Pulse Dose and Famotidine. Clin J Oncol Nurs 2007; 11:513-9. [PMID: 17723964 DOI: 10.1188/07.cjon.513-519] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
High-dose, continuous-infusion interleukin-2 (IL-2) followed by pulse dose and concurrent administration of famotidine has demonstrated response rates of 64% and 33% in patients with metastatic melanoma and metastatic renal cell carcinoma, respectively. Currently, no information is available concerning the nursing care of patients receiving that IL-2 regimen. Given the high response rates of patients on the treatment, attention by the nursing profession is warranted. Effective nursing care of patients receiving IL-2 is essential to the regimen's success. Recognition and prompt treatment of common side effects lead to better patient outcomes. This article provides nurses with an overview of the treatment regimen, expected side effects, psycho-social considerations, and discharge instructions for patients receiving continuous-infusion plus pulse IL-2 and famotidine.
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Lejeune FJ, Rimoldi D, Speiser D. New approaches in metastatic melanoma: biological and molecular targeted therapies. Expert Rev Anticancer Ther 2007; 7:701-13. [PMID: 17492933 DOI: 10.1586/14737140.7.5.701] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Classical metastatic melanoma therapy is disappointing but important progress has been made in the understanding of melanoma biology. Genetic lesions and several intracellular signaling pathways that could serve as targets for novel therapy have been identified and a number of new agents are under evaluation. Promising tumor cell targets were identified in the cell membrane, cytoplasm and nucleus. New therapeutic approaches, besides monoclonal antibodies and vaccination, include an increasing number of small molecules that have been shown to interfere restrictively with intracellular signaling pathways in melanoma and decrease proliferation, survival, migration or invasion. Other agents can interfere with stromal components of melanoma, such as angiogenesis and components of the immune system.
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Affiliation(s)
- Ferdy J Lejeune
- Ludwig Institute for Cancer Research, Division of Clinical Onco-Immunology and Centre Hospitalier Universitaire Vaudois, Department of Visceral Surgery, Lausanne, Switzerland.
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Thallinger C, Werzowa J, Poeppl W, Kovar FM, Pratscher B, Valent P, Quehenberger P, Joukhadar C. Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. J Invest Dermatol 2007; 127:2411-7. [PMID: 17508024 DOI: 10.1038/sj.jid.5700872] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.
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Affiliation(s)
- Christiane Thallinger
- Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
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Quirin C, Mainka A, Hesse A, Nettelbeck DM. Combining adenoviral oncolysis with temozolomide improves cell killing of melanoma cells. Int J Cancer 2007; 121:2801-7. [PMID: 17724714 DOI: 10.1002/ijc.23052] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. Clinical studies with first generation oncolytic adenoviruses have revealed that an increased potency is warranted in order to achieve therapeutic efficacy. One approach towards this end is to combine adenoviral oncolysis with chemotherapy. Here, a fundamental requirement is that chemotherapy does not interfere with adenovirus replication in cancer cells. We have previously developed a melanoma-targeted oncolytic adenovirus, Ad5/3.2xTyr, which features tyrosinase promoter regulated replication and enhanced cell entry into melanoma cells. In this study, we investigated a combination treatment of melanoma cells with Ad5/3.2xTyr and temozolomide (TMZ), which produces the same active metabolite as Dacarbazine/DTIC, the standard chemotherapy for advanced melanoma. We report that TMZ does not inhibit adenovirus replication in melanoma cells. Additive or synergistic cell killing of melanoma cells, dependent on the cell line used, was observed. Enhanced cell binding was not responsible for synergism of adenoviral oncolysis and TMZ treatment. We rather observed that higher numbers of virus genomes are produced in TMZ-treated cells, which also showed a cell cycle arrest in the G2 phase. Our results have important implications for the clinical implementation of adenoviral oncolysis for treatment of malignant melanoma. It suggests that such studies are feasible in the presence of TMZ or DTIC chemotherapy and recommends the investigation of a viro-chemo combination therapy.
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Affiliation(s)
- Christina Quirin
- Virotherapy Lab, Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
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Grabacka M, Plonka PM, Urbanska K, Reiss K. Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt. Clin Cancer Res 2006; 12:3028-36. [PMID: 16707598 DOI: 10.1158/1078-0432.ccr-05-2556] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well. We previously reported the antimetastatic activity of the PPARalpha ligand, fenofibrate, against melanoma tumors in vivo. Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. EXPERIMENTAL DESIGN Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARalpha expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. RESULTS Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar. These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal-regulated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. CONCLUSIONS Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.
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Affiliation(s)
- Maja Grabacka
- Center for Neurovirology, Department of Neuroscience, School of Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA
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Sato A, Ohtsuki M, Hata M, Kobayashi E, Murakami T. Antitumor Activity of IFN-λ in Murine Tumor Models. THE JOURNAL OF IMMUNOLOGY 2006; 176:7686-94. [PMID: 16751416 DOI: 10.4049/jimmunol.176.12.7686] [Citation(s) in RCA: 158] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
IFN-lambda 1, -lambda 2 and -lambda 3 have been discovered as the latest members of the class II cytokine family and shown to possess antiviral activity. Murine B16 melanoma and Colon26 cancer cells were transduced with mouse IFN-lambda to determine whether IFN-lambda possesses antitumor activity. Overexpression of IFN-lambda induced cell surface MHC class I expression and Fas/CD95 Ag, induced significant caspase-3/7 activity, and increased p21(Waf1/Cip1) and dephosphorylated Rb (Ser(780)) in B16 cells in vitro. IFN-lambda expression in tumor cell lines markedly inhibited s.c. and metastatic tumor formation in vivo compared with mock transfections (p < 0.05). Moreover, IFN-lambda expression induced lymphocytic infiltrates, and an Ab-mediated immune cell depletion assay showed that NK cells were critical to IFN-lambda-mediated tumor growth inhibition. Hydrodynamic injection of IFN-lambda cDNA successfully targeted liver metastatic foci of Colon26 cells, and moderately decreased the mortality of mice with tumors. IFN-lambda overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity, and suggested the activation of innate immune responses. Thus, IFN-lambda induced both tumor apoptosis and NK cell-mediated immunological tumor destruction through innate immune responses. These findings suggested that local delivery of IFN-lambda might prove a useful adjunctive strategy in the clinical treatment of human malignancies.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- COS Cells
- Cell Line, Tumor
- Chlorocebus aethiops
- Cytokines/biosynthesis
- Cytokines/genetics
- Cytokines/physiology
- Cytotoxicity, Immunologic
- Genetic Vectors
- Growth Inhibitors/physiology
- Interferon-gamma/administration & dosage
- Interferon-gamma/biosynthesis
- Interferon-gamma/genetics
- Interferon-gamma/physiology
- Killer Cells, Natural/cytology
- Killer Cells, Natural/immunology
- Liver Neoplasms, Experimental/immunology
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/prevention & control
- Liver Neoplasms, Experimental/secondary
- Lung Neoplasms/prevention & control
- Lung Neoplasms/secondary
- Lymphocyte Count
- Male
- Melanoma, Experimental
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- NIH 3T3 Cells
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/prevention & control
- Receptors, Interferon/biosynthesis
- Receptors, Interferon/genetics
- Skin Neoplasms/immunology
- Skin Neoplasms/prevention & control
- T-Lymphocyte Subsets/cytology
- T-Lymphocyte Subsets/immunology
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Affiliation(s)
- Atsuko Sato
- Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Shimotsuke, Tochigi, Japan
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Crook TB, Jones OM, John TG, Rees M. Hepatic resection for malignant melanoma. Eur J Surg Oncol 2006; 32:315-7. [PMID: 16364589 DOI: 10.1016/j.ejso.2005.10.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2005] [Accepted: 10/20/2005] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Patients with metastatic melanoma have a poor prognosis with a median survival of approximately 6 months. There is a paucity of data regarding the natural history of the disease in the small subset of patients who are suitable for hepatic resection for metastatic disease confined to the liver. PATIENTS AND METHODS Five patients were identified from a prospectively collected database of over 1000 liver resections performed in Basingstoke between 1986 and 2004. Clinical details and survival were analysed. RESULTS Two patients died within 12 months of resection from extrahepatic disease. The other three patients are alive and disease-free at 76, 92 and 147 months, respectively. DISCUSSION In carefully selected cases, hepatic resection for metastatic melanoma to the liver can result in long-term survival. Criteria for selection of patients as suitable for resection remain unclear.
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Affiliation(s)
- T B Crook
- Hepatobiliary Unit, The North Hampshire Hospital, Aldermaston Road, Basingstoke RG24 9NA, UK
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