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Wang S, Yu Z, Du P, Cao Y, Yang X, Ma J, Tang X, Zhang Q, Yang Y. Combination of hyperthermia and intravesical chemotherapy for the treatment of pT1 stage bladder cancer: A retrospectively clinical study. Asia Pac J Clin Oncol 2024; 20:228-233. [PMID: 36656047 DOI: 10.1111/ajco.13931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/27/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
PURPOSE To evaluate the efficiency and safety of combined local bladder hyperthermia and intravesical chemotherapy (IVC) for the treatment of patients with pT1 stage bladder cancer. METHOD A total of 189 patients with pT1 who underwent transurethral resection of bladder cancer (TURBT) were retrospectively reviewed. After TURBT, the patients with low-grade urothelial carcinoma (UC) were treated with either an IVC with pirarubicin (THP) protocol or chemo-thermotherapy (CHT) with THP protocol, whereas patients with high-grade UC were treated with either an intravesical immunotherapy (IVI) with bacillus Calmette-Guerin (BCG) protocol or CHT protocol, patients' characteristics, tumor biological features, and follow-up data were analyzed and compared between CHT and IVC group in low-grade UC, CHT, and IVI group in high-grade UC, respectively. RESULTS The median follow-up time was 24 months. In patients with low-grade UC, the median recurrence free survival (RFS) interval and costs of treatment in CHT group were significantly higher than those in IVC group (p = .01, p < .001, respectively), CHT was associated with higher RFS compared with IVC by Kaplan-Meier analysis, and three patients in IVC group upgraded to high grade when tumor recurred, whereas no cases were found upgraded in CHT group, p = .38. In patients with high-grade UC, tumor recurrence rates at 12 (p = .004) and 24 months (p = .004) after TURBT, rate of complications (p = .04)-especially for hematuresis (p = .03) and irritation symptoms (p = .04)-the median costs of treatment (p < .001) in CHT group were significantly lower than those in IVI group, RFS interval, health-related quality of life) at 12 and 24 months after TURBT in CHT group was significantly higher than those in IVI group (p < .001, p = .002, and p < .001, respectively), and CHT was associated with higher RFS compared with IVI by Kaplan-Meier analysis. The rate of patients upstaged to pT2 in CHT group seemed lower than that in IVI group, but there was no significantly statistical difference (14.3% vs. 24%, p = .58). CONCLUSION CHT has a beneficial prophylactic effect in patients with pT1 bladder cancer, especially in patients with high-grade UC, which is much more effective and safer than BCG, meanwhile it costs less compared with BCG.
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Affiliation(s)
- Shuo Wang
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ziyi Yu
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Peng Du
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yudong Cao
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao Yang
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jinchao Ma
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaohu Tang
- Urological Department, Western Beijing Cancer Hospital, Beijing, China
| | - Qi Zhang
- Urological Department, Western Beijing Cancer Hospital, Beijing, China
| | - Yong Yang
- Key Laboratory of Carcinogenesis and Translational Research (Mninistry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China
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Almehdi AM, Soliman SSM, El-Shorbagi ANA, Westwell AD, Hamdy R. Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors. Int J Mol Sci 2023; 24:14656. [PMID: 37834104 PMCID: PMC10572575 DOI: 10.3390/ijms241914656] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/16/2023] [Accepted: 08/20/2023] [Indexed: 10/15/2023] Open
Abstract
The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1-6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.
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Affiliation(s)
- Ahmed M. Almehdi
- College of Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates;
- Research Institute for Science and Engineering (RISE), University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Sameh S. M. Soliman
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates;
- College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates;
| | | | - Andrew D. Westwell
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, Cardiff CF10 3NB, UK
| | - Rania Hamdy
- Research Institute for Science and Engineering (RISE), University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates;
- Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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Ponciri Fructus Immatarus Sensitizes the Apoptotic Effect of Hyperthermia Treatment in AGS Gastric Cancer Cells through ROS-Dependent HSP Suppression. Biomedicines 2023; 11:biomedicines11020405. [PMID: 36830941 PMCID: PMC9953356 DOI: 10.3390/biomedicines11020405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Gastric cancer has been associated with a high incidence and mortality, accompanied by a poor prognosis. Given the limited therapeutic options to treat gastric cancer, alternative treatments need to be urgently developed. Hyperthermia therapy is a potentially effective and safe treatment option for cancer; however, certain limitations need to be addressed. We applied 43 °C hyperthermia to AGS gastric cancer cells combined with Ponciri Fructus Immaturus (PF) to establish their synergistic effects. Co-treatment with PF and hyperthermia synergistically suppressed AGS cell proliferation by inducing extrinsic and intrinsic apoptotic pathways. Additionally, PF and hyperthermia suppressed factors related to metastasis. Cell cycle arrest was determined by flow cytometry, revealing that co-treatment induced arrest at the G2/M phase. As reactive oxygen species (ROS) are critical in hyperthermia therapy, we next examined changes in ROS generation. Co-treatment with PF and hyperthermia increased ROS levels, and apoptotic induction mediated by this combination was partially dependent on ROS generation. Furthermore, heat shock factor 1 and heat shock proteins (HSPs) were notably suppressed following co-treatment with PF and hyperthermia. The HSP-regulating effect was also dependent on ROS generation. Overall, these findings suggest that co-treatment with PF and hyperthermia could afford a promising anticancer therapy for gastric cancer.
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Muacevic A, Adler JR, Winetz JA. Hyperthermic Extracorporeal Applied Tumor Therapy for Six Cycles for Recurrent Metastatic Peritoneal Serous Papillary Carcinoma. Cureus 2023; 15:e34100. [PMID: 36699105 PMCID: PMC9870298 DOI: 10.7759/cureus.34100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2023] [Indexed: 01/25/2023] Open
Abstract
An elderly female with failed third-line peritoneal serous papillary carcinoma with metastasis (ovarian cancer) was treated by our proprietary method of whole-body hyperthermia-a recirculating extracorporeal circuit at 42°C for 120 minutes. She received six cycles, 28 days apart. Five index lesions were measured prior to and after each treatment. Results showed stable disease with reduced standard uptake volume. She then restarted six cycles of a previously failed chemotherapy, resulting in no evidence of disease for nine months; she survived for 27 months. Using our technology, the patient experienced an improvement in the quality of life and an increase in survival.
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Hyperthermia Treatment as a Promising Anti-Cancer Strategy: Therapeutic Targets, Perspective Mechanisms and Synergistic Combinations in Experimental Approaches. Antioxidants (Basel) 2022; 11:antiox11040625. [PMID: 35453310 PMCID: PMC9030926 DOI: 10.3390/antiox11040625] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 02/04/2023] Open
Abstract
Despite recent developments in diagnosis and treatment options, cancer remains one of the most critical threats to health. Several anti-cancer therapies have been identified, but further research is needed to provide more treatment options that are safe and effective for cancer. Hyperthermia (HT) is a promising treatment strategy for cancer because of its safety and cost-effectiveness. This review summarizes studies on the anti-cancer effects of HT and the detailed mechanisms. In addition, combination therapies with anti-cancer drugs or natural products that can effectively overcome the limitations of HT are reviewed because HT may trigger protective events, such as an increase of heat shock proteins (HSPs). In the 115 reports included, the mechanisms related to apoptosis, cell cycle, reactive oxygen species, mitochondrial membrane potential, DNA damage, transcription factors and HSPs were considered important. This review shows that HT is an effective inducer of apoptosis. Moreover, the limitations of HT may be overcome using combined therapy with anti-cancer drugs or natural products. Therefore, appropriate combinations of such agents with HT will exert maximal effects to treat cancer.
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Forika G, Kiss E, Petovari G, Danko T, Gellert AB, Krenacs T. Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines. Pathol Oncol Res 2021; 27:1610048. [PMID: 34955688 PMCID: PMC8702438 DOI: 10.3389/pore.2021.1610048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/17/2021] [Indexed: 12/09/2022]
Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is frequently associated to high treatment resistance. Gemcitabine (GEM) alone or in combination is the most used chemotherapy for unresecable PDACs. Here we studied whether modulated electro-hyperthermia (mEHT), a non-invasive complementary treatment, can support the effect of GEM on PDAC cells in vitro. The LD20 for the GEM-resistant Panc1 cells proved to be 200× higher than for the drug-sensitive Capan1. The mEHT alone caused significant apoptosis in Capan1 cultures as confirmed by the elevated SubG1 phase cell fraction and increased number of cleaved Caspase-3 positive cells 48 h after treatment, with an additive effect when GEM was used after hyperthermia. These were accompanied by reduced number of G1, S, and G2/M phase cells and elevated expression of the cyclin-dependent kinase inhibitor p21waf1 protein. In GEM-resistant Panc1 cells, an initial apoptosis was detected by flow cytometry 24 h after mEHT ± GEM treatment, which however diminished by 48 h at persistent number of cleaved Caspase-3 positive tumor cells. Though GEM monotherapy reduced the number of tumor progenitor colonies in Capan1 cell line, an additive colony inhibitory effect of mEHT was observed after mEHT + GEM treatment. The heat shock induced Hsp27 and Hsp70 proteins, which are known to sensitize PDAC cells to GEM were upregulated in both Capan1 and Panc1 cells 24 h after mEHT treatment. The level of E-Cadherin, a cell adhesion molecule, increased in Capan1 cells after mEHT + GEM treatment. In conclusion, in GEM-sensitive PDAC cells mEHT treatment alone induced cell death and cell cycle inhibition and improved GEM efficiency in combination, which effects were milder and short-term up to 24 h in the GEM-resistant Panc1 cells. Our data further support the inclusion of hyperthermia, in particular of mEHT, into the traditional oncotherapy regimens of PDAC.
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Affiliation(s)
- Gertrud Forika
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Eva Kiss
- 1st Department of Internal Medicine and Oncology, Oncology Profile, Semmelweis University, Budapest, Hungary
| | - Gabor Petovari
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Titanilla Danko
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Aron Bertram Gellert
- Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary
| | - Tibor Krenacs
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- *Correspondence: Tibor Krenacs,
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Lee SY, Fiorentini G, Szasz AM, Szigeti G, Szasz A, Minnaar CA. Quo Vadis Oncological Hyperthermia (2020)? Front Oncol 2020; 10:1690. [PMID: 33014841 PMCID: PMC7499808 DOI: 10.3389/fonc.2020.01690] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022] Open
Abstract
Heating as a medical intervention in cancer treatment is an ancient approach, but effective deep heating techniques are lacking in modern practice. The use of electromagnetic interactions has enabled the development of more reliable local-regional hyperthermia (LRHT) techniques whole-body hyperthermia (WBH) techniques. Contrary to the relatively simple physical-physiological concepts behind hyperthermia, its development was not steady, and it has gone through periods of failures and renewals with mixed views on the benefits of heating seen in the medical community over the decades. In this review we study in detail the various techniques currently available and describe challenges and trends of oncological hyperthermia from a new perspective. Our aim is to describe what we believe to be a new and effective approach to oncologic hyperthermia, and a change in the paradigm of dosing. Physiological limits restrict the application of WBH which has moved toward the mild temperature range, targeting immune support. LRHT does not have a temperature limit in the tumor (which can be burned out in extreme conditions) but a trend has started toward milder temperatures with immune-oriented goals, developing toward immune modulation, and especially toward tumor-specific immune reactions by which LRHT seeks to target the malignancy systemically. The emerging research of bystander and abscopal effects, in both laboratory investigations and clinical applications, has been intensified. Our present review summarizes the methods and results, and discusses the trends of hyperthermia in oncology.
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Affiliation(s)
- Sun-Young Lee
- Department of Radiation Oncology, Chonbuk National University Hospital, Jeonbuk, South Korea
| | | | - Attila Marcell Szasz
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Gyula Szigeti
- Innovation Center, Semmelweis University, Budapest, Hungary
| | - Andras Szasz
- Biotechnics Department, St. Istvan University, Godollo, Hungary
| | - Carrie Anne Minnaar
- Department of Radiation Oncology, Wits Donald Gordon Medical Center, Johannesburg, South Africa
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8
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Combination Therapy with Cinnamaldehyde and Hyperthermia Induces Apoptosis of A549 Non-Small Cell Lung Carcinoma Cells via Regulation of Reactive Oxygen Species and Mitogen-Activated Protein Kinase Family. Int J Mol Sci 2020; 21:ijms21176229. [PMID: 32872198 PMCID: PMC7504317 DOI: 10.3390/ijms21176229] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the largest cause of cancer-induced deaths. Non-small cell lung cancer (NSCLC) is the most frequently observed subtype of lung cancer. Although recent studies have provided many therapeutic options, there is still a need for effective and safe treatments. This paper reports the combined effects of cinnamaldehyde (CNM), a flavonoid from cinnamon, together with hyperthermia, a therapeutic option for cancer treatment, on the A549 NSCLC cell line. A hyperthermia treatment of 43 °C potentiated the cytotoxicity of CNM in A549 cells. This was attributed to an increase in the apoptosis markers and suppression of the survival/protective factors, as confirmed by Western blot assays. Flow cytometry supported this result because the apoptotic profile, cell health profile, and cell cycle profile were regulated by CNM and hyperthermia combination therapy. The changes in reactive oxygen species (ROS) and its downstream target pathway, mitogen-activated protein kinases (MAPK), were evaluated. The CNM and hyperthermia combination increased the generation of ROS and MAPK phosphorylation. N-acetylcysteine (NAC), a ROS inhibitor, abolished the apoptotic events caused by CNM and hyperthermia co-treatment, suggesting that the cytotoxic effect was dependent of ROS signaling. Therefore, we suggest CNM and hyperthermia combination as an effective therapeutic option for the NSCLC treatment.
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Sen K, Sheppe AEF, Singh I, Hui WW, Edelmann MJ, Rinaldi C. Exosomes released by breast cancer cells under mild hyperthermic stress possess immunogenic potential and modulate polarization in vitro in macrophages. Int J Hyperthermia 2020; 37:696-710. [PMID: 32568583 PMCID: PMC8694666 DOI: 10.1080/02656736.2020.1778800] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 12/21/2022] Open
Abstract
Macrophages play a dual role in tumor initiation and progression, with both tumor-promoting and tumor-suppressive effects; hence, it is essential to understand the distinct responses of macrophages to tumor progression and therapy. Mild hyperthermia has gained importance as a therapeutic regimen against cancer due to its immunogenic nature, efficacy, and potential synergy with other therapies, yet the response of macrophages to molecular signals from hyperthermic cancer cells has not yet been clearly defined. Due to limited response rate of breast cancer to conventional therapeutics the development, and understanding of alternative therapies like hyperthermia is pertinent. In order to determine conditions corresponding to mild thermal dose, cytotoxicity of different hyperthermic temperatures and treatment durations were tested in normal murine macrophages and breast cancer cell lines. Examination of exosome release in hyperthermia-treated cancer cells revealed enhanced efflux and a larger size of exosomes released under hyperthermic stress. Exposure of naïve murine macrophages to exosomes released from 4T1 and EMT-6 cells posthyperthermia treatment, led to an increased expression of specific macrophage activation markers. Further, exosomes released by hyperthermia-treated cancer cells had increased content of heat shock protein 70 (Hsp70). Together, these results suggest a potential immunogenic role for exosomes released from cancer cells treated with mild hyperthermia.
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Affiliation(s)
- Kacoli Sen
- Department of Chemical Engineering, University of Florida, Gainesville, USA
| | - Austin E. F. Sheppe
- Department of Microbiology and Cell Science, University of Florida, Gainesville, USA
| | - Ishita Singh
- Department of Chemical Engineering, University of Florida, Gainesville, USA
| | - Winnie W. Hui
- Department of Microbiology and Cell Science, University of Florida, Gainesville, USA
| | - Mariola J. Edelmann
- Department of Microbiology and Cell Science, University of Florida, Gainesville, USA
| | - Carlos Rinaldi
- Department of Chemical Engineering, University of Florida, Gainesville, USA
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, USA
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Tan WP, Longo TA, Inman BA. Heated Intravesical Chemotherapy: Biology and Clinical Utility. Urol Clin North Am 2019; 47:55-72. [PMID: 31757301 DOI: 10.1016/j.ucl.2019.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Non-muscle-invasive bladder cancer can be a challenging disease to manage. In recent years, hyperthermia therapy in conjunction with intravesical therapy has been gaining traction as a treatment option for bladder cancer, especially if Bacillus Calmette-Guerin might not be available. Trials of intravesical chemotherapy with heat are few and there has been considerable heterogeneity between studies. However, multiple new trials have accrued and high-quality data are forthcoming. In this review, we discuss the role of combined intravesical hyperthermia and chemotherapy as a novel approach for the treatment of bladder cancer.
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Affiliation(s)
- Wei Phin Tan
- Division of Urology, Duke University Medical Center, Durham, NC 27710, USA
| | - Thomas A Longo
- Division of Urology, Duke University Medical Center, Durham, NC 27710, USA
| | - Brant A Inman
- Division of Urology, Duke University Medical Center, Durham, NC 27710, USA.
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Mottaghitalab F, Farokhi M, Fatahi Y, Atyabi F, Dinarvand R. New insights into designing hybrid nanoparticles for lung cancer: Diagnosis and treatment. J Control Release 2019; 295:250-267. [DOI: 10.1016/j.jconrel.2019.01.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/07/2019] [Accepted: 01/09/2019] [Indexed: 12/22/2022]
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杨 洋, 赵 妍, 马 胜, 杨 道. [Microwave Hyperthermia Combined with Gemcitabine Inhibits Proliferation
and Induces Apoptosis of Human Lung Squamous Carcinoma Cells]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2018; 21:805-814. [PMID: 30454541 PMCID: PMC6247007 DOI: 10.3779/j.issn.1009-3419.2018.11.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/29/2018] [Accepted: 07/28/2018] [Indexed: 11/05/2022]
Abstract
BACKGROUND Lung cancer is one of the highest morbidity and mortality in the world and it is very important to find an effective anti-tumor method. Microwave hyperthermia, a new treatment technology, has been getting more and more attention. This study was designed to investigate the effects of microwave hyperthermia combined with gemcitabine on the proliferation and apoptosis of human lung squamous cell carcinoma (NCI-H1703 and NCI-H2170) in vitro. METHODS The proliferation of cells treated with microwave hyperthermia, the effect of gemcitabine on cell proliferation and the proliferation of cells treated with different methods of microwave hyperthermia and gemcitabine were detected by CCK-8 assay. Colony formation assay was used to measure the colony formation of human lung squamous cell carcinoma cells. Flow cytometry assay was used to detect the total apoptosis rates of the treated cells. Caspase-3, Caspase-8 activity assay was used to detect the activity of Caspase-3, Caspase-8 enzyme in each group of cells. CCK-8 assay was used to detect the effect of control group, AC-DEVD (Caspase-3 inhibitor) group, thermalization combined group, and thermal AC-DEVD combined group on cell proliferation. The levels of p53, Caspase-3, Cleaved-Caspase-3, PARP, Bax and BCL-2 protein expression were detected using Western blot assay. RESULTS Our results demonstrated that microwave hyperthermia inhibited the proliferation of lung squamous cell carcinoma. The IC₅₀ values of gemcitabine for the two cells were 8.89 μmol/L and 44.18 μmol/L, respectively. The first chemotherapy after microwave hyperthermia has synergistic effect on the two lung squamous cell carcinoma cells and can significantly inhibit the cell clone formation (P<0.001), promote cell apoptosis (P<0.001) and increase Caspase-3 enzyme activity (P<0.001). However, it has no effect on Caspase-8 enzyme activity (P>0.05). Furthermore, Western blot analysis showed that microwave hyperthermia combined with gemcitabine could up-regulate the p53, Caspase-3, Cleaved-Caspase-3, Cleaved-PARP and Bax protein expression. CONCLUSIONS Microwave hyperthermia combined with gemcitabine remarkably inhibit the proliferation and induce apoptosis of human lung squamous cell carcinoma in vitro. This effect may be associated with the activation of p53, cleavage of PARP protein, and induced the Caspase-3 dependent apoptosis.
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Affiliation(s)
- 洋 杨
- 450002 郑州，郑州大学第一附属医院放疗科Department of Radiation Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, China
| | - 妍妍 赵
- 310006 杭州，杭州市第一人民医院，浙江大学医学院附属杭州市第一人民医院转化医学中心Affiliated Hangzhou First People' s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - 胜林 马
- 310006 杭州，杭州市第一人民医院，浙江大学医学院附属杭州市第一人民医院转化医学中心Affiliated Hangzhou First People' s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - 道科 杨
- 450002 郑州，郑州大学第一附属医院放疗科Department of Radiation Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, China
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Krzykawska-Serda M, Ho JCS, Ware MJ, Law JJ, Newton JM, Nguyen L, Agha M, Curley SA, Corr SJ. Ultrasound Doppler as an Imaging Modality for Selection of Murine 4T1 Breast Tumors for Combination Radiofrequency Hyperthermia and Chemotherapy. Transl Oncol 2018; 11:864-872. [PMID: 29763773 PMCID: PMC6019683 DOI: 10.1016/j.tranon.2018.04.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 04/13/2018] [Accepted: 04/17/2018] [Indexed: 12/18/2022] Open
Abstract
Noninvasive radiofrequency-induced (RF) hyperthermia has been shown to increase the perfusion of chemotherapeutics and nanomaterials through cancer tissue in ectopic and orthotopic murine tumor models. Additionally, mild hyperthermia (37°C-45°C) has previously shown a synergistic anticancer effect when used with standard-of-care chemotherapeutics such as gemcitabine and Abraxane. However, RF hyperthermia treatment schedules remain unoptimized, and the mechanisms of action of hyperthermia and how they change when treating various tumor phenotypes are poorly understood. Therefore, pretreatment screening of tumor phenotypes to identify key tumors that are predicted to respond more favorably to hyperthermia will provide useful mechanistic data and may improve therapeutic outcomes. Herein, we identify key biophysical tumor characteristics in order to predict the outcome of combinational RF and chemotherapy treatment. We demonstrate that ultrasound imaging using Doppler mode can be utilized to predict the response of combinational RF and chemotherapeutic therapy in a murine 4T1 breast cancer model.
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Affiliation(s)
- Martyna Krzykawska-Serda
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA; Jagiellonian University, Dept. Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Krakow, Poland.
| | | | - Matthew J Ware
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA
| | - Justin J Law
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA
| | - Jared M Newton
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA; Baylor College of Medicine, Interdepartmental Program in Translational Biology and Molecular Medicine, Houston, TX, USA
| | - Lam Nguyen
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA
| | - Mahdi Agha
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA
| | - Steven A Curley
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA; Rice University, Dept. of Mechanical Engineering and Materials Science, Houston, TX, USA
| | - Stuart J Corr
- Baylor College of Medicine, Dept. of Surgery, Houston, TX, USA; University of Houston, Dept. of Biomedical Engineering, Houston, TX, USA; Rice University, Dept. of Chemistry and Smalley-Curl Institute, Houston, TX, USA; Swansea University, Medical School, Swansea, Wales, UK.
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Cesna V, Sukovas A, Jasukaitiene A, Naginiene R, Barauskas G, Dambrauskas Z, Paskauskas S, Gulbinas A. Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells. World J Gastroenterol 2018; 24:1072-1083. [PMID: 29563752 PMCID: PMC5850127 DOI: 10.3748/wjg.v24.i10.1072] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/02/2018] [Accepted: 01/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the response to hyperthermia and chemotherapy, analyzing apoptosis, cytotoxicity, and cisplatin concentration in different digestive system cancer cells. METHODS AGS (gastric cancer cell line), Caco-2 (colon cancer cell line) and T3M4 (pancreatic cancer cell line) were treated by cisplatin and different temperature setting (37 °C to 45 °C) either in isolation, or in combination. Treatment lasted for one hour. 48 h after the treatment viability was evaluated by MTT, cell apoptosis by Annexin V-PE and 7ADD flow cytometry. Intracellular cisplatin concentration was measured immediately after the treatment, using mass spectrometry. Isobologram analysis was performed to evaluate the mathematical combined effect of temperature and cisplatin. RESULTS AGS cells were the most sensitive to isolated application of hyperthermia. Hyperthermia, in addition to cisplatin treatment, did not provoke a synergistic effect at intervals from 37 °C to 41 °C in neither cancer cell line. However, a temperature of 43 °C enhanced cisplatin cytotoxicity for Caco-2 cells. Moreover, isobologram analysis revealed mathematical antagonistic effects of cisplatin and temperature combined treatment in AGS cells; variations between synergistic, additive, and antagonistic effects in Caco-2 cells; and additive and antagonistic effects in T3M4 cells. Combined treatment enhanced initiation of cell apoptosis in AGS, Caco-2, and T3M4 cells by 61%, 20%, and 19% respectively. The increase of intracellular cisplatin concentration was observed at 43 °C by 30%, 20%, and 18% in AGS, Caco-2, and T3M4 cells, respectively. CONCLUSION In addition to cisplatin, hyperthermia up to 43 °C does not affect the viability of cancer cells in a synergistic manner.
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Affiliation(s)
- Vaidotas Cesna
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Arturas Sukovas
- Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Aldona Jasukaitiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Rima Naginiene
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Giedrius Barauskas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Zilvinas Dambrauskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Saulius Paskauskas
- Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania
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van der Heijden AG, Dewhirst MW. Effects of hyperthermia in neutralising mechanisms of drug resistance in non-muscle-invasive bladder cancer. Int J Hyperthermia 2016; 32:434-45. [DOI: 10.3109/02656736.2016.1155761] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Kirui DK, Celia C, Molinaro R, Bansal SS, Cosco D, Fresta M, Shen H, Ferrari M. Mild hyperthermia enhances transport of liposomal gemcitabine and improves in vivo therapeutic response. Adv Healthc Mater 2015; 4:1092-103. [PMID: 25721343 PMCID: PMC4433418 DOI: 10.1002/adhm.201400738] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 01/17/2015] [Indexed: 12/11/2022]
Abstract
Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery, and antitumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment leads to a threefold increase in accumulation of 80-nm liposomes and enhances spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment lead to a threefold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg kg(-1) Gem Lip leads to a twofold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect is confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg kg(-1) Gem Lip achieves similar therapeutic efficacy as the use of 60 mg kg(-1) free gemcitabine. In conclusion, improvements in vivo efficacy are demonstrated resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines.
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Affiliation(s)
- Dickson K Kirui
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
| | - Christian Celia
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
- Department of Pharmacy, University of Chieti – Pescara “G. d’Annunzio”, Chieti, 66013, Italy
| | - Roberto Molinaro
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
- Department of Health Sciences, University of Catanzaro “Magna Graecia”, Germaneto – Catanzaro, 88100, Italy
| | - Shyam S. Bansal
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
| | - Donato Cosco
- Department of Health Sciences, University of Catanzaro “Magna Graecia”, Germaneto – Catanzaro, 88100, Italy
| | - Massimo Fresta
- Department of Health Sciences, University of Catanzaro “Magna Graecia”, Germaneto – Catanzaro, 88100, Italy
| | - Haifa Shen
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
- Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY, 10065, USA
| | - Mauro Ferrari
- Department of NanoMedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas, 77030, USA
- Department of Biomedical Engineering in Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
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Raoof M, Zhu C, Cisneros BT, Liu H, Corr SJ, Wilson LJ, Curley SA. Hyperthermia inhibits recombination repair of gemcitabine-stalled replication forks. J Natl Cancer Inst 2014; 106:dju183. [PMID: 25128695 DOI: 10.1093/jnci/dju183] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gemcitabine is a potent nucleoside analogue against solid tumors, but development of drug resistance is a substantial problem. Removal of gemcitabine incorporated into DNA by repair mechanisms may contribute to resistance in chemo-refractory solid tumors. Human hepatocellular carcinoma (HCC) is usually very chemoresistant to gemcitabine. METHODS We treated HCC in vitro and in vivo (orthotopic murine model with human Hep3B or HepG2 xenografts, 7-10 CB17SCID mice per group) with gemcitabine. The role of homologous recombination repair proteins in repairing stalled replication forks was evaluated with hyperthermia exposure and cell-cycle analysis. The Student t-test was used for two-sample comparisons. Multiple group data were analyzed using one-way analysis of variance. All statistical tests were two-sided. RESULTS We demonstrated that Mre11-mediated homologous recombination repair of gemcitabine-stalled replication forks is crucial to survival of HCC cells. Furthermore, we demonstrated inhibition of Mre11 by an exonuclease inhibitor or concomitant hyperthermia. In orthotopic murine models of chemoresistant HCC, the Hep3B tumor mass with radiofrequency plus gemcitabine treatment (mean ± SD, 180±91mg) was statistically significantly smaller compared with gemcitabine alone (661±419mg, P = .0063). CONCLUSIONS This study provides mechanistic understanding of homologous recombination inhibiting-strategies, such as noninvasive radiofrequency field-induced hyperthermia, to overcome resistance to gemcitabine in refractory human solid tumors.
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Affiliation(s)
- Mustafa Raoof
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Cihui Zhu
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Brandon T Cisneros
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Heping Liu
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Stuart J Corr
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Lon J Wilson
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC)
| | - Steven A Curley
- Department of Surgery, University of Arizona, Tucson, AZ (MR); Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MR, CZ, BTC, HL, SJC, SAC); Department of Surgery, Baylor College of Medicine, Houston, TX (SAC, SJC); Department of Chemistry, Rice University, Houston, TX (LJW, SJC).
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Raoof M, Corr SJ, Zhu C, Cisneros BT, Kaluarachchi WD, Phounsavath S, Wilson LJ, Curley SA. Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2014; 10:1121-30. [PMID: 24650884 PMCID: PMC4349335 DOI: 10.1016/j.nano.2014.03.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 02/23/2014] [Accepted: 03/05/2014] [Indexed: 12/26/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P<0.05). In animal experiments, targeted gold nanoconjugates halted the growth of subcutaneous Hep3B xenografts in combination with RF exposure (P<0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ~275-fold lower than the current clinically-delivered systemic dose of gemcitabine. FROM THE CLINICAL EDITOR In a model of hepatocellular carcinoma, the authors demonstrate that non-invasive RF-induced hyperthermia applied with cetuximab targeted delivery of Au NP-gemcitabine conjugate is more effective and safe at dosages ~ 275-fold lower than the current clinically-used systemic dose of gemcitabine.
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MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/chemistry
- Antibodies, Monoclonal, Humanized/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Cetuximab
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/chemistry
- Deoxycytidine/therapeutic use
- Drug Delivery Systems
- Gold/chemistry
- Gold/therapeutic use
- Humans
- Hyperthermia, Induced
- Liver/drug effects
- Liver/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Metal Nanoparticles/chemistry
- Metal Nanoparticles/therapeutic use
- Mice, Inbred BALB C
- Nanoconjugates/chemistry
- Nanoconjugates/therapeutic use
- Gemcitabine
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Affiliation(s)
- Mustafa Raoof
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Stuart J Corr
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Chemistry and Richard E. Smalley Institute for Nanoscale Science & Technology, Rice University, Houston, TX, USA
| | - Cihui Zhu
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Brandon T Cisneros
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Chemistry and Richard E. Smalley Institute for Nanoscale Science & Technology, Rice University, Houston, TX, USA
| | | | - Sophia Phounsavath
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Chemistry and Richard E. Smalley Institute for Nanoscale Science & Technology, Rice University, Houston, TX, USA
| | - Lon J Wilson
- Department of Chemistry and Richard E. Smalley Institute for Nanoscale Science & Technology, Rice University, Houston, TX, USA
| | - Steven A Curley
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Mechanical Engineering and Materials Science Rice University, Houston, TX, USA.
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Ballard-Croft C, Wang D, Rosenstein K, Wang J, Pollock R, Morris JA, Zwischenberger JB. Venovenous perfusion-induced systemic hyperthermia: five-day sheep survival studies. J Thorac Cardiovasc Surg 2014; 148:2360-6. [PMID: 24908352 DOI: 10.1016/j.jtcvs.2014.04.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 04/08/2014] [Accepted: 04/24/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Since hyperthermia selectively kills lung cancer cells, we developed a venovenous perfusion-induced systemic hyperthermia system for advanced lung cancer therapy. Our objective was to test the safety and accuracy of our venovenous perfusion-induced systemic hyperthermia system in 5-day sheep survival studies, following Good Laboratory Practice standards. METHODS Our venovenous perfusion-induced systemic hyperthermia system, which included a double-lumen cannula (Avalon Elite, Rancho Dominguez, Calif), a centrifugal pump (Bio-Pump 560; Medtronic Inc, Minneapolis, Minn), a heat exchanger (BIOtherm; Medtronic Perfusion Systems, Brooklyn Park, Minn), and a heater/cooler (modified Blanketrol IIIl Cincinnati Subzero, Cincinnati, Ohio), was tested in healthy adult sheep (n=5). The perfusion circuit was primed with prewarmed Plasma-Lyte A (Baxter Healthcare Corp, Deerfield, Ill) and de-aired. Calibrated temperature probes were placed in the right and left sides of the nasopharynx, bladder, and blood in/out tubing in the animal. The double-lumen cannula was inserted through the jugular vein into the superior vena cava, with the tip in the inferior vena cava. RESULTS Therapeutic core temperature (42°C-42.5°C), calculated from the right and left sides of the nasopharynx and bladder temperatures, was achieved in all sheep. Heating time was 21±5 minutes. Therapeutic core temperature was maintained for 120 minutes followed by a cooling phase (35±6 minutes) to reach baseline temperature. All sheep recovered from anesthesia with spontaneous breathing within 4 hours. Arterial, pulmonary, and central venous pressures were stable. Transient increases in heart rate, cardiac output, and blood glucose occurred during hyperthermia but returned to normal range after venovenous perfusion-induced systemic hyperthermia termination. Electrolytes, complete blood counts, and metabolism enzymes were within normal to near normal range throughout the study. No significant venovenous perfusion-induced systemic hyperthermia-related hemolysis was observed. Neurologic assessment showed normal brain function all 5 days. CONCLUSIONS Our venovenous perfusion-induced systemic hyperthermia system safely delivered the hyperthermia dose with no significant hyperthermia-related complications.
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Affiliation(s)
- Cherry Ballard-Croft
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky
| | - Dongfang Wang
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky.
| | - Kyle Rosenstein
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky
| | - Jingkun Wang
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky
| | - Robert Pollock
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky
| | - J Ann Morris
- Department of Surgery, University of Kentucky College of Medicine, Lexington, Ky
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Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications. Acta Biomater 2014; 10:2622-9. [PMID: 24486913 DOI: 10.1016/j.actbio.2014.01.025] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 01/02/2014] [Accepted: 01/21/2014] [Indexed: 11/22/2022]
Abstract
One of the current challenges in the systemic delivery of nanoparticles in cancer therapy applications is the lack of effective tumor localization. Iron oxide nanoparticles (IONPs) coated with crosslinked dextran were functionalized with the tumor-homing peptide CREKA, which binds to fibrinogen complexes in the extracellular matrix of tumors. This allows for the homing of these nanoparticles to tumor tissue. The IONP core allows for particle heating upon exposure to an alternating magnetic field (AMF), while the dextran coating stabilizes the particles in suspension and decreases the cytotoxicity of the system. Magnetically mediated hyperthermia (MMH) allows for the heating of tumor tissue to increase the efficacy of traditional cancer treatments using IONPs. While MMH provides the opportunity for localized heating, this method is currently limited by the lack of particle penetration into tumor tissue, even after effective targeted delivery to the tumor site. The CREKA-conjugated nanoparticles presented were characterized for their size, stability, heating capabilities and biocompatibility. The particles had a hydrated diameter of 52nm, were stable in phosphate buffered saline solution and media with 10% v/v fetal bovine serum over at least 12h, and generated enough heat to raise solution temperatures well into the hyperthermia range (41-45°C) when exposed to an AMF, owing to an average specific absorption rate of 83.5Wg(-1). Cytotoxicity studies demonstrated that the particles have low cytotoxicity over long exposure times at low concentrations. A fibrinogen clotting assay was used to determine the binding affinity of CREKA-conjugated particles, which was significantly greater than the binding affinity of dextran, only coated IONPs demonstrating the potential for this particle system to effectively home to a variety of tumor locations. Finally, it was shown that in vitro MMH increased the effects of cisplatin compared with cisplatin or MMH treatments alone.
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Szasz A. Current status of oncothermia therapy for lung cancer. THE KOREAN JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2014; 47:77-93. [PMID: 24782955 PMCID: PMC4000888 DOI: 10.5090/kjtcs.2014.47.2.77] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 03/24/2014] [Accepted: 03/28/2014] [Indexed: 11/22/2022]
Abstract
Lung cancer is one of the most common malignant tumors, and it has the highest death rate. Oncothermia is a feasible and successful treatment for lung cancer. Results show a remarkable survival benefit for patients, with a good quality of life. The treatment has no, or in some cases mild, side-effects and could decrease the adverse effects of the complementary treatment. Applying oncothermia together with other treatment methods could increase the effects and result in better performance. A comparison of studies demonstrates a good correspondence in the data, which strengthens the reliability of the studies, and clearly shows the feasibility of the application of oncothermia to treating all kinds of pulmonary malignancies including non-small-cell and small-cell primary tumors, and all of the metastatic diseases of the pulmonary system.
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Affiliation(s)
- Andras Szasz
- Department of Biotechnics, St. Istvan University, Godollo, Hungary
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22
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Kirui DK, Mai J, Palange AL, Qin G, van de Ven AL, Liu X, Shen H, Ferrari M. Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors. PLoS One 2014; 9:e86489. [PMID: 24558362 PMCID: PMC3928046 DOI: 10.1371/journal.pone.0086489] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 12/09/2013] [Indexed: 01/03/2023] Open
Abstract
Background Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur. Results In this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm2) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion. Conclusions Our findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.
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Affiliation(s)
- Dickson K. Kirui
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Juahua Mai
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Anna-Lisa Palange
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Guoting Qin
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Anne L. van de Ven
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Xuewu Liu
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Haifa Shen
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
- Department of Cell and Development Biology, Weill Cornell Medical College, New York, New York, United States of America
| | - Mauro Ferrari
- Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America
- Department of Internal Medicine, Weill Cornell Medical College, New York, New York, United States of America
- * E-mail:
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Kirui DK, Koay EJ, Guo X, Cristini V, Shen H, Ferrari M. Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2013; 10:1487-96. [PMID: 24262998 DOI: 10.1016/j.nano.2013.11.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 10/04/2013] [Accepted: 11/05/2013] [Indexed: 01/14/2023]
Abstract
The abnormal tumor vasculature presents a major challenge to the adequate delivery of chemotherapeutics, often limiting efficacy. We developed a nanoparticle-based technique to deliver localized mild hyperthermia (MHT) used to transiently alter tumor vascular transport properties and enhance transport of macromolecules into tumor interstitium. The strategy involved administering and localizing accumulation of stealth gold nanorods (GNRs, 103 μg of GNRs/g of tumor), and irradiating tumor with a low-photon laser flux (1 W/cm(2)) to generate MHT. The treatment increased vascular permeability within 24 h after treatment, allowing enhanced transport of macromolecules up to 54 nm in size. A mathematical model is used to describe changes in tumor mass transport properties where the rate of macromolecular exchange between interstitial and vascular region (R) and maximum dye enhancement (Ymax) of 23-nm dextran dye is analytically solved. During enhanced permeability, R increased by 200% while Ymax increased by 30% relative to untreated group in pancreatic CAPAN-1 tumors. MHT treatment also enhanced transport of larger dextran dye (54 nm) as assessed by intravital microscopy, without causing occlusive cellular damage. Enhanced vascular transport was prolonged for up to 24 h after treatment, but reversible with transport parameters returning to basal levels after 36 h. This study indicates that localized mild hyperthermia treatment opens a transient time-window with which to enable and augment macromolecule transport and potentially improve therapeutic efficacy. From the clinical editor: In this study, local intra-tumor mild hyperthermia is induced using a nanoparticle-based approach utilizing stealth gold nanorods and irradiating the tumor with low-photon laser flux, resulting in locally increased vascular permeability enabling enhanced delivery of therapeutics, including macromolecules up to 54 nm in size. Similar approaches would be very helpful in addressing treatment-resistant malignancies in clinical practice.
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Affiliation(s)
| | - Eugene J Koay
- Houston Methodist Research Institute, Houston, TX, USA; MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaojing Guo
- Houston Methodist Research Institute, Houston, TX, USA; Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, Tianjin, China
| | - Vittorio Cristini
- Department of Chemical and Nuclear Engineering, Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM, USA
| | - Haifa Shen
- Houston Methodist Research Institute, Houston, TX, USA; Weill Cornell Medical College, New York, NY, USA
| | - Mauro Ferrari
- Houston Methodist Research Institute, Houston, TX, USA; Weill Cornell Medical College, New York, NY, USA.
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Torres-Lugo M, Rinaldi C. Thermal potentiation of chemotherapy by magnetic nanoparticles. Nanomedicine (Lond) 2013; 8:1689-707. [PMID: 24074390 PMCID: PMC4001113 DOI: 10.2217/nnm.13.146] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Clinical studies have demonstrated the effectiveness of hyperthermia as an adjuvant for chemotherapy and radiotherapy. However, significant clinical challenges have been encountered, such as a broader spectrum of toxicity, lack of patient tolerance, temperature control and significant invasiveness. Hyperthermia induced by magnetic nanoparticles in high-frequency oscillating magnetic fields, commonly termed magnetic fluid hyperthermia, is a promising form of heat delivery in which thermal energy is supplied at the nanoscale to the tumor. This review discusses the mechanisms of heat dissipation of iron oxide-based magnetic nanoparticles, current methods and challenges to deliver heat in the clinic, and the current work related to the use of magnetic nanoparticles for the thermal-chemopotentiation of therapeutic drugs.
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Affiliation(s)
- Madeline Torres-Lugo
- Department of Chemical Engineering, University of Puerto Rico, Mayaguez Campus, PO BOX 9000, Mayaguez, PR 00681, Puerto Rico.
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Hyperthermia as adjunct to intravesical chemotherapy for bladder cancer. BIOMED RESEARCH INTERNATIONAL 2013; 2013:262313. [PMID: 24073396 PMCID: PMC3773892 DOI: 10.1155/2013/262313] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/01/2013] [Indexed: 01/03/2023]
Abstract
Nonmuscle invasive bladder cancer remains a very costly cancer to manage because of high recurrence rates requiring long-term surveillance and treatment. Emerging evidence suggests that adjunct and concurrent use of hyperthermia with intravesical chemotherapy after transurethral resection of bladder tumor further reduces recurrence risk and progression to advanced disease. Hyperthermia has both direct and immune-mediated cytotoxic effect on tumor cells including tumor growth arrest and activation of antitumor immune system cells and pathways. Concurrent heat application also acts as a sensitizer to intravesical chemotherapy agents. As such the ability to deliver hyperthermia to the focus of tumor while minimizing damage to surrounding benign tissue is of utmost importance to optimize the benefit of hyperthermia treatment. Existing chemohyperthermia devices that allow for more localized heat delivery continue to pave the way in this effort. Current investigational methods involving heat-activated drug delivery selectively to tumor cells using temperature-sensitive liposomes also offer promising ways to improve chemohyperthermia efficacy in bladder cancer while minimizing toxicity to benign tissue. This will hopefully allow more widespread use of chemohyperthermia to all bladder cancer patients, including metastatic bladder cancer.
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Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application. ASAIO J 2013; 59:390-6. [PMID: 23820278 DOI: 10.1097/mat.0b013e318291d0a5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment.
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Kirui DK, Khalidov I, Wang Y, Batt CA. Targeted near-IR hybrid magnetic nanoparticles for in vivo cancer therapy and imaging. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2013; 9:702-11. [DOI: 10.1016/j.nano.2012.11.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 11/04/2012] [Accepted: 11/18/2012] [Indexed: 11/25/2022]
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Physiologic response to a simplified venovenous perfusion-induced systemic hyperthermia system. ASAIO J 2013; 58:601-6. [PMID: 23085942 DOI: 10.1097/mat.0b013e318271badb] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Our original venovenous perfusion-induced systemic hyperthermia (vv-PISH) system appeared to significantly improve the survival of patients with lung cancer, but was too complex with numerous dialysis problems. We tested a simplified vv-PISH circuit that includes the Avalon Elite (Avalon Laboratories, LLC, Rancho Dominguez, CA) double lumen cannula, a modified heat exchanger, a water heater/cooler, and a centrifugal pump. The purpose of this study was to evaluate this simplified vv-PISH system (without hemodialyzer) and to investigate the physiologic response to whole-body hyperthermia in pigs. We tested our vv-PISH circuit in healthy adult female swine (n = 7, 55-68 kg). The therapeutic core temperature (42°C), calculated as mean of rectal, bladder, and esophageal temperatures, was achieved in six swine. A maximum difference of 0.5°C was observed between the individual temperature sensor readings, indicating homogeneous heat distribution. Heart rate and mean arterial pressure were transiently altered, but were safely managed. A significant elevation in pulmonary artery pressure occurred during the heating phase, resulting in death of one pig. In all other pigs, pulmonary artery pressure returned to physiologic values during the therapeutic phase. Arterial blood electrolytes were maintained without the need of a dialyzer. Major organ function was within normal parameters. The simplified vv-PISH circuit reliably delivered the hyperthermic dose with no need of dialysis.
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WANG LIN, LIU XINKUI, WU YONGJUN, WU WEIDONG, WU YIMING. Involvement of ROS in the inhibitory effect of thermotherapy combined with chemotherapy on A549 human lung adenocarcinoma cell growth through the Akt pathway. Oncol Rep 2012; 28:1369-75. [DOI: 10.3892/or.2012.1954] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Accepted: 05/31/2012] [Indexed: 11/06/2022] Open
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Shen H, Li XD, Wu CP, Yin YM, Wang RS, Shu YQ. The regimen of gemcitabine and cisplatin combined with radio frequency hyperthermia for advanced non-small cell lung cancer: A phase II study. Int J Hyperthermia 2010; 27:27-32. [DOI: 10.3109/02656736.2010.500645] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Jia D, Liu J. Current devices for high-performance whole-body hyperthermia therapy. Expert Rev Med Devices 2010; 7:407-23. [PMID: 20420562 DOI: 10.1586/erd.10.13] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
For late-stage cancer, whole-body hyperthermia (WBH) is highly regarded by physicians as a promising alternative to conventional therapies. Although WBH is still under scrutiny due to potential toxicity, its benefits are incomparable, as diversified devices and very promising treatment protocols in this area are advanced into Phase II and III clinical trials. Following the introduction of the WBH principle, this paper comprehensively reviews the state-of-art high-performance WBH devices based on the heat induction mechanisms - radiation, convection and conduction. Through analyzing each category's physical principle and heat-induction property, the advantages and disadvantages of the devices are evaluated. Technical strategies and critical scientific issues are summarized. For future developments, research directions worth pursuing are presented in this article.
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Affiliation(s)
- Dewei Jia
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, PR China
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Adachi S, Kokura S, Okayama T, Ishikawa T, Takagi T, Handa O, Naito Y, Yoshikawa T. Effect of hyperthermia combined with gemcitabine on apoptotic cell death in cultured human pancreatic cancer cell lines. Int J Hyperthermia 2009; 25:210-9. [PMID: 19437237 DOI: 10.1080/02656730802657036] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND AND AIM It is reported that NF-kappaB is activated by chemotherapy in some cancer cell lines and NF-kappaB activation is one of the mechanisms by which tumors are induced to become resistant to chemotherapy. We reported that heat-treatment-induced heat shock protein 70 (Hsp70) could inhibit I-kappa-B kinase, resulting in the inhibition of NF-kappaB activation. Therefore, we speculated that activated NF-kappaB in a pancreatic cell line might be inhibited by heat treatment, resulting in the enhancement of gemcitabine-induced cytotoxicity. METHODS We used the human pancreatic carcinoma cell lines AsPC-1 and MIAPaCa-2. Both cell lines were treated with various concentrations (0, 5, 10, 20, and 30 microM) of gemcitabine for 24 h. Heat treatment (43 degrees C, 1 h) was performed at various times relative to gemcitabine treatment. The effect of gemcitabine and heat treatment on cell survival was determined by WST-8 assay. The status of NF-kappaB in carcinoma cells exposed to gemcitabine was investigated by electrophoretic mobility shift assay and immunocytochemistry. We analyzed apoptosis and necrosis in AsPC-1 and MIAPaCa-2 cells by flow cytometry. Furthermore, the levels of Hsp70, cyclin D1, caspase-3, and vascular endothelial growth factor in each treatment group were detected by western blotting. RESULTS (1) Significant cytotoxicity was observed with gemcitabine. (2) Gemcitabine activated NF-kappaB binding activity in both cell lines. (3) Heat treatment inhibited the gemcitabine-induced activation of NF-kappaB. (4) Heat treatment enhanced the cytotoxicity of gemcitabine, especially when heat treatment was performed 24 h before gemcitabine was given. (5) The levels of Hsp70 were increased by heat treatment. Gemcitabine did not affect the protein level of Hsp70. The levels of pro-caspase-3 were decreased by heat treatment combined with gemcitabine. CONCLUSIONS Heat treatment inhibited gemcitabine-induced activation of NF-kappaB, resulting in the enhancement of the cytotoxicity of gemcitabine.
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Affiliation(s)
- Satoko Adachi
- Department of Inflammation and Immunology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Ponce AM, Vujaskovic Z, Yuan F, Needham D, Dewhirst MW. Hyperthermia mediated liposomal drug delivery. Int J Hyperthermia 2009; 22:205-13. [PMID: 16754340 DOI: 10.1080/02656730600582956] [Citation(s) in RCA: 184] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Drug delivery systems have been developed for cancer therapy in an attempt to increase the tumour drug concentration while limiting systemic exposure. Liposomes have achieved passive targeting of solid tumours through enhanced vascular permeability, which is greatly augmented by hyperthermia. However, anti-tumour efficacy has often been limited by slow release of bioavailable drug within the tumour. Local hyperthermia has become the most widely used stimulus for triggered release of liposomal drugs, through the use of specific lipids, polymers or other modifiers. A temperature-sensitive liposome containing doxorubicin has been shown to release 100% of contents through stabilized membrane pores within 10-20 s at 41 degrees C. This formulation has exhibited dramatic improvements in pre-clinical drug delivery and tumour regression and is now in clinical trials. Significantly, recent studies show that this liposome, in combination with local hyperthermia, exhibits vascular shutdown as a mechanism of anti-tumour effect that is not observed with free doxorubicin.
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Affiliation(s)
- Ana M Ponce
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
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Bull JMC, Strebel FR, Jenkins GN, Deng W, Rowe RW. The importance of schedule in whole body thermochemotherapy. Int J Hyperthermia 2009; 24:171-81. [DOI: 10.1080/02656730701883212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Affiliation(s)
- J. M. C. Bull
- The Division of Oncology, The Department of Internal Medicine, The University of Texas Medical School at Houston, TexasUSA
| | - F. R. Strebel
- The Division of Oncology, The Department of Internal Medicine, The University of Texas Medical School at Houston, TexasUSA
| | - G. N. Jenkins
- The Division of Oncology, The Department of Internal Medicine, The University of Texas Medical School at Houston, TexasUSA
| | - W. Deng
- The Division of Oncology, The Department of Internal Medicine, The University of Texas Medical School at Houston, TexasUSA
| | - R. W. Rowe
- The Division of Oncology, The Department of Internal Medicine, The University of Texas Medical School at Houston, TexasUSA
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Ohguri T, Imada H, Yahara K, Narisada H, Morioka T, Nakano K, Korogi Y. Concurrent chemoradiotherapy with gemcitabine plus regional hyperthermia for locally advanced pancreatic carcinoma: initial experience. ACTA ACUST UNITED AC 2009; 26:587-96. [PMID: 19132489 DOI: 10.1007/s11604-008-0279-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2008] [Accepted: 09/02/2008] [Indexed: 01/10/2023]
Abstract
PURPOSE The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CRT) with gemcitabine plus regional hyperthermia (HT) for locally advanced pancreatic carcinoma (LAPC). MATERIALS AND METHODS A total of 29 patients with LAPC treated with concurrent CRT using gemcitabine were retrospectively analyzed. Radiotherapy was administered with a median total dose of 61.2 Gy. Of the 29 patients, 20 (69%) also underwent regional HT during CRT (CRHT group). The remaining 9 patients did not receive regional HT (CRT group) because of a common bile duct stent placement, patient refusal, older age, or obesity. The efficacy and toxicity of the treatments and the predictors of good outcome were evaluated. RESULTS The median disease progression-free and overall survival times were significantly better for the CRHT group than for the CRT group (8.8 vs. 4.9 months, P = 0.02, and 18.6 vs. 9.6 months, P = 0.01), respectively. Grade 3-4 hematological toxicities for the CRHT group were detected in eight patients (40%) and grade 3 nonhematologic toxicity in one (diarrhea). CONCLUSION Concurrent CRT using gemcitabine with regional HT may be a feasible and promising regimen for LAPC, and the results justified further evaluation in a large number of patients to confirm its definite benefit.
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Affiliation(s)
- Takayuki Ohguri
- Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Japan.
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Moulin M, Carpentier S, Levade T, Arrigo AP. Potential roles of membrane fluidity and ceramide in hyperthermia and alcohol stimulation of TRAIL apoptosis. Apoptosis 2007; 12:1703-20. [PMID: 17610065 DOI: 10.1007/s10495-007-0096-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
We recently reported that a mild heat shock induces a long lasting stimulation of TRAIL-induced apoptosis of leukemic T-lymphocytes and myeloid cell lines, but not normal T-lymphocytes, which correlates with an enhanced ability of TRAIL to recognize its receptors. As shown here, this phenomenon could be inhibited by the xanthogenate agent D609, a sphingomyelin/ceramide pathway inhibitor. A caspase-dependent and D609-sensitive two-fold increase in ceramide level was elicited by heat shock plus TRAIL combined treatment. One day after heat shock, a similar increase in ceramide was induced by TRAIL. Sphingolipids/ceramides are known to regulate membrane integrity, and heat shock increases membrane fluidity. In this regard, the heat shock plus TRAIL combined treatment resulted in a D609-sensitive membrane fluidization which was far more intense than that induced by heat shock only. We also report that membrane fluidizers, that mimic the effect of heat shock, such benzyl alcohol and ethanol, potently stimulated TRAIL-induced apoptosis. As heat shock, these alcohols increased, in a D609-sensitive manner, membrane fluidity in the presence of TRAIL, the recognition of TRAIL death receptors, and ceramide levels. These results suggest that stress agents that trigger ceramide production and an overall increase in membrane fluidity are stimulators of TRAIL apoptosis.
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Affiliation(s)
- Maryline Moulin
- Laboratoire Stress, Chaperons et Mort cellulaire, CNRS UMR 5534, Centre de Génétique Moléculaire et Cellulaire, Université Claude Bernard, Lyon-1, 16 rue Dubois, 69622 Villeurbanne Cedex, France
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Myhr G. MR guided cancer treatment system for an elevated therapeutic index - a macroscopic approach. Med Hypotheses 2007; 70:665-70. [PMID: 17765401 DOI: 10.1016/j.mehy.2007.06.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2007] [Accepted: 06/30/2007] [Indexed: 10/22/2022]
Abstract
Adjuvant therapy for cancer usually refers to surgery followed by chemotherapy and/or radiation treatment to decrease the risk of recurrence. But still, the absolute benefit for survival obtained with adjuvant therapy compared with control is only approximately 6%. The objective of this analysis is to formulate a non-invasive multimodal cancer treatment system related to cancer stem cells and hypoxic fractions of solid tumors, emphasizing MRI monitoring and guidance, to elevate the therapeutic index. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of drugs and radiotherapy, where well oxygenated cells requiring one third of the dose of hypoxic cells to achieve a given level of cell killing. Cancer stem cells might be the cause of tumor recurrence, sometimes many years after the appearance of the successful treatment of a primary tumor. Thus, the primary objective of such a treatment system will be to provide sufficient selective toxicity to both kill cancer stem cells and cells of hypoxic fractions of the tumor. Active tumor targeting with the use of liposomally encapsulated drugs is the starting point of the treatment procedure. The system facilitates quality assurance means by MR monitoring of drug accumulation and drug release, in real time. Cavitation involves the nucleation, growth and oscillation of gaseous cavities. Selective drug release and/or hyperthermia are achieved by ultrasound induced cavitation well defined to the tumor region. Hyperthermic effects, increased vascularization and subsequent increase in pO2 levels to hypoxic regions, can be monitored by MRI. MRI monitoring of key physiological parameters facilitates optimization related to approximate real time concomitant treatments, including correct timing and various combinations of drug therapy, hyperthermia, ionizing radiation, ablation, other treatment options, before or after surgery. The likelihood of an improved therapeutic index with the use of such a system seems compelling. Further research related to optimal timing, combinations of responses between liposomally encapsulated drug dosage, ultrasound exposure, hyperthermia, pO2 response time, ionizing radiation fractionation and treatment time, have to be conducted.
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Affiliation(s)
- Gunnar Myhr
- CancerCure Technology Ltd., PO Box 7159 Majorstuen, 0307 Oslo, Norway.
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de Bree E, Tsiftsis DD. Experimental and pharmacokinetic studies in intraperitoneal chemotherapy: from laboratory bench to bedside. RECENT RESULTS IN CANCER RESEARCH. FORTSCHRITTE DER KREBSFORSCHUNG. PROGRES DANS LES RECHERCHES SUR LE CANCER 2007; 169:53-73. [PMID: 17506249 DOI: 10.1007/978-3-540-30760-0_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Herakleion, Greece
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