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Russell M, Wilkinson M, Hayes A. Isolated Limb Perfusion for Extremity Soft Tissue Sarcoma and Malignant Melanoma. Indian J Surg Oncol 2024; 15:499-508. [PMID: 39239444 PMCID: PMC11371996 DOI: 10.1007/s13193-024-01920-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 03/03/2024] [Indexed: 09/07/2024] Open
Abstract
Isolated limb perfusion (ILP) is a regional chemotherapy technique used in the treatment of locally advanced or unresectable extremity soft tissue sarcoma (ESTS) or malignant melanoma (MM) of the limbs. It allows for high concentrations of chemotherapeutic agents to be perfused in the limb while minimising the risk of systemic side-effects. While the technique has been utilized for decades, the role of ILP has evolved as other treatment strategies have become available. Current indications for ILP in sarcoma include induction in unresectable ESTS to allow for future definitive limb preservation procedures as well as definitive treatment of unresectable, multifocal ESTS. In MM, ILP is typically used in unresectable in-transit melanoma, and rarely as an alternative to amputation in bulky, symptomatic extremity disease. This review seeks to summarise the current evidence base and indications for ILP as well as present some technical insights from a high-volume United Kingdom (UK) unit.
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Affiliation(s)
- Michael Russell
- Sarcoma and Melanoma Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Michelle Wilkinson
- Sarcoma and Melanoma Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Andrew Hayes
- Sarcoma and Melanoma Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
- Institute of Cancer Research, 237 Fulham Road, London, SW3 6JJ UK
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Wang MJ, Xia Y, Gao QL. DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy. Curr Med Sci 2024; 44:261-272. [PMID: 38561595 DOI: 10.1007/s11596-024-2859-1] [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: 12/15/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024]
Abstract
DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.
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Affiliation(s)
- Meng-Jie Wang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yu Xia
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Qing-Lei Gao
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Fawzy RM, Abdel-Aziz AA, Bassiouny K, Fayed AM. Phytocompounds-based therapeutic approach: Investigating curcumin and green tea extracts on MCF-7 breast cancer cell line. J Genet Eng Biotechnol 2024; 22:100339. [PMID: 38494270 PMCID: PMC10980874 DOI: 10.1016/j.jgeb.2023.100339] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
BACKGROUND Breast cancer (BC) has transcended lung cancer as the most common cancer in the world. Due to the disease's aggressiveness, rapid growth, and heterogeneity, it is crucial to investigate different therapeutic approaches for treatment. According to the World Health Organization (WHO), Plant-based therapeutics continue to be utilized as safe/non-toxic complementary or alternative treatments for cancer, even in developed countries, regardless of how cutting-edge conventional therapies are. Despite their low bioavailability, curcumin (CUR) and green tea (GT) represent safer therapeutic options. Due to their potent molecular-modulating properties on various cancer-related molecules and signaling pathways, they are considered gold-standard therapeutic agents and have been incorporated into the development of one or more therapeutic strategies of BC treatment. METHODS We investigated the modulatory role of CUR and GT extracts on significant multi molecular targets in MCF-7 BC cell line to assess their potential as BC multi-targeting agents. We analyzed the phytocompounds in GT leaves using High-performance liquid chromatography (HPLC) and Gas chromatography-mass spectrometry (GC-MS) techniques. The mRNA expression levels of Raf-1, Telomerase, Tumor necrosis factor alpha (TNF-α) and Interleukin-8 (IL-8) genes in MCF-7 cells were quantified using quantitative real-time PCR (qRT-PCR). The cytotoxicity of the extracts was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the released Lactate dehydrogenase (LDH), a valuable marker for identifying the programmed necrosis (necroptosis). Additionally, the concentrations of the necroptosis-related proinflammatory cytokines (TNF-α and IL-8) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS In contrast to the GT, the results showed the anticancer and cytotoxic properties of CUR against MCF-7 cells, with a relatively higher level of released LDH. The CUR extract downregulated the oncogenic Raf-1, suppressed the Telomerase and upregulated the TNF-α and IL-8 genes. Results from the ELISA showed a notable increase in IL-8 and TNF-α cytokines levels after CUR treatment, which culminated after 72 h. CONCLUSIONS Among both extracts, only CUR effectively modulated the understudy molecular targets, achieving multi-targeting anticancer activity against MCF-7 cells. Moreover, the applied dosage significantly increased levels of the proinflammatory cytokines, which represent a component of the cytokines-targeting-based therapeutic strategy. However, further investigations are recommended to validate this therapeutic approach.
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Affiliation(s)
- Radwa M Fawzy
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt.
| | - Amal A Abdel-Aziz
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
| | - Khalid Bassiouny
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
| | - Aysam M Fayed
- Department of Molecular Biology, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Sadat City, Egypt
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Devarkonda V, Balmuri S, Akabane MACC, Akabane H. Adalimumab-associated Philadelphia chromosome positive acute lymphoblastic leukaemia in a patient with Crohn's disease. BMJ Case Rep 2023; 16:e255604. [PMID: 37879713 PMCID: PMC10603484 DOI: 10.1136/bcr-2023-255604] [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] [Indexed: 10/27/2023] Open
Abstract
The US Food and Drug Administration has approved TNF(Tumor necrosis factor) alpha inhibitors to manage a range of inflammatory conditions, including Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other inflammatory disorders. However, these inhibitors can potentially increase the risk of secondary blood malignancies due to TNF alpha's role in various cellular processes such as angiogenesis, cell cycle proliferation, apoptosis and differentiation. In this article, we present a unique case study of a patient who developed Philadelphia-positive acute lymphoblastic leukaemia (ALL) while receiving adalimumab, a potent monoclonal antibody that specifically binds to TNF-alpha. We describe the patient's successful treatment using standard-of-care chemotherapy and tyrosine kinase inhibitors, resulting in complete remission with no measurable residual disease. Furthermore, we conducted a literature review on this subject and identified five similar cases of ALL associated with TNF alpha inhibitors.
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Affiliation(s)
- Vishal Devarkonda
- LSU Health Shreveport School of Medicine, Shreveport, Louisiana, USA
| | - Shravya Balmuri
- LSU Health Shreveport School of Medicine, Shreveport, Louisiana, USA
| | | | - Hugo Akabane
- LSU Health Shreveport School of Medicine, Shreveport, Louisiana, USA
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Corti A, Calimeri T, Curnis F, Ferreri AJM. Targeting the Blood–Brain Tumor Barrier with Tumor Necrosis Factor-α. Pharmaceutics 2022; 14:pharmaceutics14071414. [PMID: 35890309 PMCID: PMC9315592 DOI: 10.3390/pharmaceutics14071414] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/17/2022] Open
Abstract
The blood–brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of a derivative of tumor necrosis factor-α (TNF) that can target and alter the blood–brain-tumor-barrier. This drug, called NGR-TNF, consists of a TNF molecule fused to the Cys-Asn-Gly-Arg-Cys-Gly (CNGRCG) peptide (called NGR), a ligand of aminopeptidase N (CD13)-positive tumor blood vessels. Results of preclinical studies suggest that this peptide-cytokine fusion product represents a valuable strategy for delivering TNF to tumor vessels in an amount sufficient to break the biological barriers that restrict drug penetration in cancer lesions. Moreover, clinical studies performed in patients with primary central nervous system lymphoma, have shown that an extremely low dose of NGR-TNF (0.8 µg/m2) is sufficient to promote selective blood–brain-tumor-barrier alteration, increase the efficacy of R-CHOP (a chemo-immunotherapy regimen) and improve patient survival. Besides reviewing these findings, we discuss the potential problems related to the instability and molecular heterogeneity of NGR-TNF and review the various approaches so far developed to obtain more robust and homogeneous TNF derivatives, as well as the pharmacological properties of other peptide/antibody-TNF fusion products, muteins and nanoparticles that are potentially useful for targeting the blood–brain tumor barrier. Compared to other TNF-related drugs, the administration of extremely low-doses of NGR-TNF or its derivatives appear as promising non-immunogenic approaches to overcome TNF counter-regulatory mechanism and systemic toxicity, thereby enabling safe breaking of the BBTB.
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Affiliation(s)
- Angelo Corti
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- Faculty of Medicine, Università Vita-Salute San Raffaele, 20132 Milan, Italy
- Correspondence: (A.C.); (A.J.M.F.); Tel.: +39-02-2643-4802 (A.C.); +39-02-2643-7649 (A.J.M.F.); Fax: +39-02-2643-7534 (A.J.M.F.)
| | - Teresa Calimeri
- Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
| | - Flavio Curnis
- Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
| | - Andres J. M. Ferreri
- Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- Correspondence: (A.C.); (A.J.M.F.); Tel.: +39-02-2643-4802 (A.C.); +39-02-2643-7649 (A.J.M.F.); Fax: +39-02-2643-7534 (A.J.M.F.)
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Neganova M, Liu J, Aleksandrova Y, Klochkov S, Fan R. Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment. Cancers (Basel) 2021; 13:6062. [PMID: 34885171 PMCID: PMC8657135 DOI: 10.3390/cancers13236062] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/28/2021] [Accepted: 11/28/2021] [Indexed: 01/17/2023] Open
Abstract
Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.
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Affiliation(s)
- Margarita Neganova
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Sergey Klochkov
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, China; (M.N.); (J.L.)
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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Benoot T, Piccioni E, De Ridder K, Goyvaerts C. TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer? Int J Mol Sci 2021; 22:ijms22168691. [PMID: 34445397 PMCID: PMC8395431 DOI: 10.3390/ijms22168691] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.
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The immunocytokine L19-TNF eradicates sarcomas in combination with chemotherapy agents or with immune check-point inhibitors. Anticancer Drugs 2021; 31:799-805. [PMID: 32304410 DOI: 10.1097/cad.0000000000000938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Antibody-cytokine fusion proteins (also called 'immunocytokines') represent an emerging class of biopharmaceutical products, which are being considered for cancer immunotherapy. When used as single agents, pro-inflammatory immunocytokines are rarely capable of inducing complete and durable cancer regression in mouse models and in patients. However, the combination treatment with conventional chemotherapy or with other immune-stimulatory agents typically increases the therapeutic efficacy of immunocytokines. In this article, we describe combination treatments of a tumor-targeting antibody-cytokine fusion protein based on the L19 antibody (specific to a splice isoform of fibronectin) fused to murine tumor necrosis factor with standard chemotherapy (dacarbazine, trabectedin or melphalan) or with an immune check-point inhibitor (anti-PD-1) in a BALB/c derived immunocompetent murine model of sarcoma (WEHI-164). All combination treatments led to improved tumor remission compared to single-agent treatments, suggesting that these combination partners may be suitable for further clinical development in sarcoma patients.
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Effect of Nardostachys jatamansi DC. on Apoptosis, Inflammation and Oxidative Stress Induced by Doxorubicin in Wistar Rats. PLANTS 2020; 9:plants9111579. [PMID: 33203171 PMCID: PMC7734586 DOI: 10.3390/plants9111579] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
The study aimed to investigate the protective action of jatamansi (Nardostachys jatamansi DC.) against doxorubicin cardiotoxicity. Methanolic extract of jatamansi (MEJ) was prepared and standardized using HPTLC fingerprinting, GC-MS chemoprofiling, total phenolic content, and antioxidant activity in vitro. Further in vivo activity was evaluated using rodent model. Animals were divided into five groups (n = 6) namely control (CNT) (Normal saline), toxicant (TOX, without any treatment), MEJ at low dose (JAT1), MEJ at high dose (JAT2), and standard desferrioxamine (STD). All groups except control received doxorubicin 2.5 mg per Kg intra-peritoneally for 3 weeks in twice a week regimen. After 3 weeks, the blood samples and cardiac tissues were collected from all groups for biochemical and histopathological evaluation. Treatment with MEJ at both dose levels exhibited significant reduction (p < 0.001 vs. toxicant) of serum CK-MB (heart creatine kinase), LDH (Lactate dehydrogenase) & HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) levels, and tissue MDA (melondialdehyde) level; insignificant difference was observed (p > 0.05) in TNF-alpha (tumour necrosis factor), IL-6 (interleukine-6) levels and caspase activity as compared to TOX. Histopathological evaluation of cardiac tissues of different treatment groups further reinforced the findings of biochemical estimation. This study concludes that jatamansi can protect cardiac tissues from oxidative stress-induced cell injury and lipid peroxidation as well as against inflammatory and apoptotic effects on cardiac tissues.
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Seynhaeve A, Amin M, Haemmerich D, van Rhoon G, ten Hagen T. Hyperthermia and smart drug delivery systems for solid tumor therapy. Adv Drug Deliv Rev 2020; 163-164:125-144. [PMID: 32092379 DOI: 10.1016/j.addr.2020.02.004] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 12/31/2022]
Abstract
Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.
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11
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Guo L, Zhang Y, Wei R, Wang C, Feng M. Lipopolysaccharide-anchored macrophages hijack tumor microtube networks for selective drug transport and augmentation of antitumor effects in orthotopic lung cancer. Am J Cancer Res 2019; 9:6936-6948. [PMID: 31660078 PMCID: PMC6815965 DOI: 10.7150/thno.37380] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/06/2019] [Indexed: 12/17/2022] Open
Abstract
Objective: Engineered immune cells (e.g., therapeutic T cells) provide a revolutionary approach to combat cancer. Certain activated immune cells can exquisitely sense and respond to the tumor microenvironment. Here, we propose a paradigm based on engineering macrophages to allow selective intercellular drug delivery and augmentation of antitumor activities by hijacking tumor microtube networks. Methods: Macrophages were engineered via anchoring lipopolysaccharides on the plasma membrane (LM). The tumor tropism of LM encapsulating doxorubicin (LM-Dox) was monitored by a real-time cell migration assay and small animal in vivo imaging. Monocyte chemoattractant protein-1 (CCL2) was measured by quantitative PCR and ELISA. Intercellular conduit formation was characterized by confocal laser scanning microscopy and scanning electron microscopy. LM-Dox activation of tumor-associated macrophages to release TNF-α was evaluated by western blot and immunofluorescence assays. The potential therapeutic effects of LM-Dox in a 3D tumor-immune model and a murine orthotopic lung cancer model were tested. Results: LM-Dox exhibited tumor tropism in response to CCL2 produced by A549 lung tumor cells and lung tumor tissues resulting in a remarkably higher amount of tumor accumulation than the case of Lipo-Dox (~ 4-fold). Intriguingly, LM-Dox accumulated at tumor sites hijacked the established tumor microtube networks and even stimulated microtube formation with tumor cells but not with normal cells to enable selective and rapid transport of the drug to tumor cells. Simultaneously, LM-Dox induced secretion of TNF-α in tumor-associated macrophages, which increased the antitumor activity of Dox. Thus, LM-Dox increased the inhibitory effects on tumor growth and metastasis in a mouse orthotopic lung cancer model and minimized the side effects of Dox-induced tumor invasion. Conclusion: Lipopolysaccharide-anchored macrophages that can hijack tumor microtube networks for selective drug transport may serve as versatile bioactive carriers of anticancer drugs. In the clinical context, these engineered microphages represent a personalized medicine approach that can be translated into potential use of patient-derived monocytes/macrophages for drug delivery by means of cell-to-cell communication.
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Lu L, Li ZJ, Li LF, Shen J, Zhang L, Li MX, Wang JH, Cho CH. Targeted low-dose TNFα delivered by TCP-1 peptide exerts differential synergistic effects on anti-cancer actions of chemotherapeutic drugs. J Drug Deliv Sci Technol 2018. [DOI: 10.1016/j.jddst.2018.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Ortega-Rivera OA, Quintanar JL, Del Toro-Arreola S, Alpuche-Solis ÁG, Esparza-Araiza MJ, Salinas E. Antitumor and immunostimulatory activities of a genotype V recombinant attenuated veterinary Newcastle disease virus vaccine. Oncol Lett 2018; 15:1246-1254. [PMID: 29399179 DOI: 10.3892/ol.2017.7387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 10/17/2017] [Indexed: 11/05/2022] Open
Abstract
Antitumor conventional treatments including chemo/radiotherapy result in several side effects and non-specificity. Therapies including the use of oncolytic viruses, particularly the Newcastle disease virus (NDV), have emerged as an attractive alternative due to their capacity to kill cancer cells directly or through stimulation of the immune system. In the present study, a commercial vaccine composed of a recombinant attenuated NDV strain P05 (rNDV-P05) was assessed for antitumor and immunostimulatory activity. Firstly, hemagglutination activity was evaluated at different pH and temperature conditions. Then, cancer cell lines and peripheral blood mononuclear cells (PBMC) were co-cultured with or without rNDV-P05 and cytoplasmic nucleosomes were measured by enzyme-linked immunosorbent assay (ELISA) as an apoptosis indicator. Antitumor cytokines produced by PBMC in response to the virus were analyzed by ELISA and reverse transcription quantitative polymerase chain reaction. Characterization of rNDV-P05 indicates that the virus is slightly sensible to acid and basic pH, and stable at temperatures no greater than 42°C. The majority of cell lines developed apoptosis in co-culture with rNDV-P05 in a dose-time dependent manner. The highest level of HeLa, HCC1954 and HepG2 cell apoptosis was at 48 h/50 hemagglutination units (HU), and HL-60 was 24 h/50 HU. A549 cell line and PBMC did not show sensitivity to apoptosis by the virus. PBMC from healthy donors stimulated with the rNDV-P05 increased significantly the levels of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α and soluble TNF-related apoptosis-inducing ligand in culture supernatants, as well as their mRNA expression. These results demonstrate that the pro-apoptotic effect of rNDV-P05 and its magnitude is specific to particular tumor cell lines and is not induced on PBMC; and the virus stimulates the expression of several key antitumor cytokines. This study promotes the use of rNDV-P05 in an alternate application of different viral strains during virotherapy with NDV.
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Affiliation(s)
- Oscar Antonio Ortega-Rivera
- Laboratory of Immunology, Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes 20131, Aguascalientes, Mexico
| | - J Luis Quintanar
- Laboratory of Neurophysiology, Department of Physiology and Pharmacology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes 20131, Aguascalientes, Mexico
| | - Susana Del Toro-Arreola
- Laboratory of Immunology, Department of Physiology, CUCS, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Ángel G Alpuche-Solis
- Division of Molecular Biology, Potosinian Institute of Scientific and Technological Research, San Luis Potosí 78216, San Luis Potosí, Mexico
| | - Mayra J Esparza-Araiza
- Division of Molecular Biology, Potosinian Institute of Scientific and Technological Research, San Luis Potosí 78216, San Luis Potosí, Mexico
| | - Eva Salinas
- Laboratory of Immunology, Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, Aguascalientes 20131, Aguascalientes, Mexico
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Kurena B, Müller E, Christopoulos PF, Johnsen IB, Stankovic B, Øynebråten I, Corthay A, Zajakina A. Generation and Functional In Vitro Analysis of Semliki Forest Virus Vectors Encoding TNF-α and IFN-γ. Front Immunol 2017; 8:1667. [PMID: 29276511 PMCID: PMC5727424 DOI: 10.3389/fimmu.2017.01667] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/14/2017] [Indexed: 12/25/2022] Open
Abstract
Cytokine gene delivery by viral vectors is a promising novel strategy for cancer immunotherapy. Semliki Forest virus (SFV) has many advantages as a delivery vector, including the ability to (i) induce p53-independent killing of tumor cells via apoptosis, (ii) elicit a type-I interferon (IFN) response, and (iii) express high levels of the transgene. SFV vectors encoding cytokines such as interleukin (IL)-12 have shown promising therapeutic responses in experimental tumor models. Here, we developed two new recombinant SFV vectors encoding either murine tumor necrosis factor-α (TNF-α) or murine interferon-γ (IFN-γ), two cytokines with documented immunostimulatory and antitumor activity. The SFV vector showed high infection rate and cytotoxicity in mouse and human lung carcinoma cells in vitro. By contrast, mouse and human macrophages were resistant to infection with SFV. The recombinant SFV vectors directly inhibited mouse lung carcinoma cell growth in vitro, while exploiting the cancer cells for production of SFV vector-encoded cytokines. The functionality of SFV vector-derived TNF-α was confirmed through successful induction of cell death in TNF-α-sensitive fibroblasts in a concentration-dependent manner. SFV vector-derived IFN-γ activated macrophages toward a tumoricidal phenotype leading to suppressed Lewis lung carcinoma cell growth in vitro in a concentration-dependent manner. The ability of SFV to provide functional cytokines and infect tumor cells but not macrophages suggests that SFV may be very useful for cancer immunotherapy employing tumor-infiltrating macrophages.
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Affiliation(s)
- Baiba Kurena
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.,Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Elisabeth Müller
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway.,Department of Biosciences, University of Oslo, Oslo, Norway
| | - Panagiotis F Christopoulos
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Ingvild Bjellmo Johnsen
- Department of Laboratory Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Branislava Stankovic
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Inger Øynebråten
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Alexandre Corthay
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Anna Zajakina
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia
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15
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Co-delivery of chemotherapeutics and proteins for synergistic therapy. Adv Drug Deliv Rev 2016; 98:64-76. [PMID: 26546464 DOI: 10.1016/j.addr.2015.10.021] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/23/2015] [Accepted: 10/26/2015] [Indexed: 01/15/2023]
Abstract
Combination therapy with chemotherapeutics and protein therapeutics, typically cytokines and antibodies, has been a type of crucial approaches for synergistic cancer treatment. However, conventional approaches by simultaneous administration of free chemotherapeutic drugs and proteins lead to limitations for further optimizing the synergistic effects, due to the distinct in vivo pharmacokinetics and distribution of small drugs and proteins, insufficient tumor selectivity and tumor accumulation, unpredictable drug/protein ratios at tumor sites, short half-lives, and serious systemic adverse effects. Consequently, to obtain optimal synergistic anti-tumor efficacy, considerable efforts have been devoted to develop the co-delivery systems for co-incorporating chemotherapeutics and proteins into a single carrier system and subsequently releasing the dual or multiple payloads at desired target sites in a more controllable manner. The co-delivery systems result in markedly enhanced blood stability and in vivo half-lives of the small drugs and proteins, elevated tumor accumulation, as well as the capability of delivering the multiple agents to the same target sites with rational drug/protein ratios, which may facilitate maximizing the synergistic effects and therefore lead to optimal antitumor efficacy. This review emphasizes the recent advances in the co-delivery systems for chemotherapeutics and proteins, typically cytokines and antibodies, for systemic or localized synergistic cancer treatment. Moreover, the proposed mechanisms responsible for the synergy of chemotherapeutic drugs and proteins are discussed.
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16
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Ham B, Fernandez MC, D’Costa Z, Brodt P. The diverse roles of the TNF axis in cancer progression and metastasis. TRENDS IN CANCER RESEARCH 2016; 11:1-27. [PMID: 27928197 PMCID: PMC5138060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Metastasis is a multi-step process that ultimately depends on the ability of disseminating cancer cells to establish favorable communications with their microenvironment. The tumor microenvironment consists of multiple and continuously changing cellular and molecular components. One of the factors regulating the tumor microenvironment is TNF-α, a pleiotropic cytokine that plays key roles in apoptosis, angiogenesis, inflammation and immunity. TNF-α can have both pro- and anti-tumoral effects and these are transmitted via two major receptors, the 55 kDa TNFR1 and the 75 kDa TNFR2 that have distinct, as well as overlapping functions. TNFR1 is ubiquitously expressed while the expression of TNFR2 is more restricted, mainly to immune cells. While TNFR1 can transmit pro-apoptotic or pro-survival signals through a complex network of downstream mediators, the role of TNFR2 is less well understood. One of its main functions is to act as a survival factor and moderate the pro-apoptotic effects of TNFR1, particularly in immune cells. In this review, we summarize the evidence for the involvement of the TNF system in the progression of the metastatic process from its contribution to the early steps of tumor cell invasion to its role in the colonization of distant sites, particularly the liver. We show how the TNF receptors each contribute to these processes by regulating and shaping the tumor microenvironment. Current evidence and concepts on the potential use of TNF targeting agents for cancer prevention and therapy are discussed.
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Affiliation(s)
- Boram Ham
- Department of Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Maria Celia Fernandez
- Department of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Zarina D’Costa
- Department of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
| | - Pnina Brodt
- Department of Medicine, McGill University and the McGill University Health Centre, Montréal, QC, Canada
- Department of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada
- Department of Oncology, McGill University and the McGill University Health Centre, Montréal, QC, Canada
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17
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Lu L, Li ZJ, Li LF, Wu WKK, Shen J, Zhang L, Chan RLY, Yu L, Liu YW, Ren SX, Chan KM, Cho CH. Vascular-targeted TNFα improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer. J Control Release 2015; 210:134-46. [PMID: 26003042 DOI: 10.1016/j.jconrel.2015.05.282] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 03/20/2015] [Accepted: 05/20/2015] [Indexed: 01/08/2023]
Abstract
Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor α (TNFα) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFα (TCP-1/TNFα: 5μg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFα, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFα (1ng/mouse) and to a greater extent by the same concentration of TCP-1/TNFα. In this regard, TCP-1/TNFα combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFα normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFα in bone marrow and spleen. At the same time, TCP-1/TNFα significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFα holds great promise for colorectal cancer therapy.
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Affiliation(s)
- Lan Lu
- Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, PR China.; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Zhi Jie Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Long Fei Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Jing Shen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Lin Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Ruby Lok Yi Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Le Yu
- School of Pharmacy, Southern Medical University, Guangzhou, PR China
| | - Ya Wei Liu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Shun Xiang Ren
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Kam Ming Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Chi Hin Cho
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
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18
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Ma X, Song Y, Zhang K, Shang L, Gao Y, Zhang W, Xue X, Jia H, Geng J, Zhou W, Dang Y, Li E, Ti X, Fan F, Zhang Y, Li M. Recombinant mutated human TNF in combination with chemotherapy for stage IIIB/IV non-small cell lung cancer: a randomized, phase III study. Sci Rep 2015; 4:9918. [PMID: 25897826 PMCID: PMC4404801 DOI: 10.1038/srep09918] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 03/23/2015] [Indexed: 11/29/2022] Open
Abstract
Tumor necrosis factor (TNF), an anti-angiogenic agent in cancer treatment, is limited
to isolated limb perfusion due to systemic toxicities. We previously prepared a TNF
mutant (rmhTNF) that significantly improved responses in lung cancer patients and
exhibited a promising safety profile in phase I and II studies. To further
investigate whether rmhTNF with standard chemotherapy provides a survival benefit,
529 patients with stage IIIB/IV non-small cell lung cancer (NSCLC) were randomly
assigned to receive docetaxel plus carboplatin/cisplatin with rmhTNF (265) or
chemotherapy alone (264). After four cycles of treatment, the median overall
survival was 13.7 months in the chemotherapy plus rmhTNF group compared with 10.3
months in the chemotherapy group (hazard ratio (HR) 0.75, P = 0.001). The
median progression-free survival in the chemotherapy plus rmhTNF group and the
chemotherapy group was 8.6 and 4.5 months (HR 0.76, P = 0.001), respectively,
with corresponding response rates of 38.5% and 27.7% (P = 0.008). Increased
hyperpyrexia and pulmonary hemorrhage were associated with rmhTNF, but most effects
were well tolerated. The results indicated that rmhTNF effectively potentiated
chemotherapy in patients with advanced NSCLC and was comparable with bevacizumab, an
angiogenesis inhibitor approved by the Food and Drug Administration (FDA) for
NSCLC.
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Affiliation(s)
- Xiaowen Ma
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Lei Shang
- Department of Health Statistics, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Yuan Gao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Xiaochang Xue
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Huimin Jia
- The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Jian Geng
- Department of Medical Oncology, General Hospital of Nanjing Military Command, Medical School of Nanjing University, Nanjing, China
| | - Wei Zhou
- General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yazheng Dang
- Cancer Center, The 323 Hospital of People's Liberation Army, Xi'an, China
| | - Enxiao Li
- Department of Medical Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Xinyu Ti
- Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Fulin Fan
- New Taihe Biopharmaceutical Co., Ltd., Guangzhou, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Meng Li
- Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
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19
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Botter SM, Neri D, Fuchs B. Recent advances in osteosarcoma. Curr Opin Pharmacol 2014; 16:15-23. [PMID: 24632219 DOI: 10.1016/j.coph.2014.02.002] [Citation(s) in RCA: 184] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/06/2014] [Accepted: 02/07/2014] [Indexed: 01/09/2023]
Abstract
Although osteosarcoma (OS) is a rare malignancy, it is ranked among the leading causes of cancer-related death in the pediatric age group. The cancer's low prevalence and its large tumor heterogeneity make it difficult to obtain meaningful progress in patient survival. In this review we present an overview of current clinical trials which largely focus on stimulation of the immune system or rely on the inhibition of kinases such as Src and mTOR. The potential efficacy of tumor-targeted TNFalpha is discussed, as well as the importance of preclinical validation of new targets. To improve the success of future clinical trials, clinicians and basic researchers need to intensify their exchange. Finally, a case is made for individualized treatment of OS patients, based on interdisciplinary cooperation in dedicated Sarcoma Centers.
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Affiliation(s)
- Sander M Botter
- Sarcoma Center & Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Forchstrasse 340, 8008 Zurich, Switzerland
| | - Dario Neri
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland
| | - Bruno Fuchs
- Sarcoma Center & Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Forchstrasse 340, 8008 Zurich, Switzerland.
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20
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Lamoureux F, Trichet V, Chipoy C, Blanchard F, Gouin F, Redini F. Recent advances in the management of osteosarcoma and forthcoming therapeutic strategies. Expert Rev Anticancer Ther 2014; 7:169-81. [PMID: 17288528 DOI: 10.1586/14737140.7.2.169] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Osteosarcoma is the most frequent primary bone tumor and occurs mainly in young patients (average age: 18 years). No evolution of the survival rates has been recorded for two decades in response to current treatment, associating often toxic and badly tolerated cures of chemotherapy (given a significant rate of bad responders) with preserving surgery. Among the proposed innovative strategies, immune-based therapy, antiangiogenesis agents, tumor-suppressor or suicide gene therapy, or anticancer drugs not commonly used in osteosarcoma are presented. A further strategy is to target the tumor microenvironment rather than the tumor itself.
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Affiliation(s)
- François Lamoureux
- Université de Nantes, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes cedex 1, France.
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21
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Corti A, Curnis F, Rossoni G, Marcucci F, Gregorc V. Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example. BioDrugs 2013; 27:591-603. [PMID: 23743670 PMCID: PMC3832761 DOI: 10.1007/s40259-013-0048-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.
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Affiliation(s)
- Angelo Corti
- Tumor Biology and Vascular Targeting Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, via Olgettina 58, 20132, Milan, Italy,
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22
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Alic L, van Vliet M, Wielopolski PA, ten Hagen TLM, van Dijke CF, Niessen WJ, Veenland JF. Regional heterogeneity changes in DCE-MRI as response to isolated limb perfusion in experimental soft-tissue sarcomas. CONTRAST MEDIA & MOLECULAR IMAGING 2013; 8:340-9. [PMID: 23613437 DOI: 10.1002/cmmi.1528] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 10/31/2012] [Accepted: 12/11/2012] [Indexed: 12/17/2022]
Abstract
Experimental evidence supports an association between heterogeneity in tumor perfusion and response to chemotherapy/radiotherapy, disease progression and malignancy. Therefore, changes in tumor perfusion may be used to assess early effects of tumor treatment. However, evaluating changes in tumor perfusion during treatment is complicated by extensive changes in tumor type, size, shape and appearance. Therefore, this study assesses the regional heterogeneity of tumors by dynamic contrast-enhanced MRI (DCE-MRI) and evaluates changes in response to isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan. Data were acquired in an experimental cancer model, using a macromolecular contrast medium, albumin-(Gd-DTPA)45. Small fragments of BN 175 (a soft-tissue sarcoma) were implanted in eight brown Norway rats. MRI of five drug-treated and three sham-treated rats was performed at baseline and 1 h after ILP intervention. Properly co-registered baseline and follow-up DCE-MRI were used to estimate the volume transfer constant (K(trans) ) pharmacokinetic maps. The regional heterogeneity was estimated in 16 tumor sectors and presented in cumulative map-volume histograms. On average, ILP-treated tumors showed a decrease in regional heterogeneity on the histograms. This study shows that heterogenic changes in regional tumor perfusion, estimated using DCE-MRI pharmacokinetic maps, can be measured and used to assess the short-term effects of a potentially curative treatment on the tumor microvasculature in an experimental soft-tissue sarcoma model.
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Affiliation(s)
- L Alic
- Erasmus MC - University Medical Centre Rotterdam, Department of Medical Informatics, Rotterdam, The Netherlands.
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23
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Micheau O, Shirley S, Dufour F. Death receptors as targets in cancer. Br J Pharmacol 2013; 169:1723-44. [PMID: 23638798 PMCID: PMC3753832 DOI: 10.1111/bph.12238] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 04/25/2013] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. LINKED ARTICLES This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.
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24
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Ten Hagen TLM, Seynhaeve ALB, de Wiel-Ambagtsheer GA, de Bruijn EA, van Tiel ST, Ruegg C, Meyring M, Grell M, Goodman SL, Eggermont AMM. The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model. Int J Cancer 2012; 132:2694-704. [PMID: 23152080 DOI: 10.1002/ijc.27940] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 10/15/2012] [Indexed: 01/13/2023]
Abstract
Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.
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Affiliation(s)
- Timo L M Ten Hagen
- Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
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25
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Chen FH, Lu N, Zhang HW, Zhao L, He LC, Sun HP, You QD, Li ZY, Guo QL. LYG-202 augments tumor necrosis factor-α-induced apoptosis via attenuating casein kinase 2-dependent nuclear factor-κB pathway in HepG2 cells. Mol Pharmacol 2012; 82:958-71. [PMID: 22909797 DOI: 10.1124/mol.112.079848] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025] Open
Abstract
Tumor necrosis factor-α (TNF-α) is being used as an antineoplastic agent in treatment regimens of patients with locally advanced solid tumors, but TNF-α alone is only marginally active. In clinical use, it is usually combined with other chemical agents to increase its tumor response rate. Our previous studies reported that LYG-202 (5-hydroxy-8-methoxy-7-(4-(4-methylpiperazin-1-yl)butoxy)-2-phenyl-4H-chromen-4-one), a synthesized flavonoid with a piperazine substitution, has antiproliferative, antiangiogenic, and proapoptotic activities in multiple cancer cell lines. Here we evaluated the antineoplastic effect of TNF-α and analyzed the mechanism underlying its combination with LYG-202. Our results indicated that LYG-202 significantly increased the cytostatic and proapoptotic activity of TNF-α in HepG2 cells and heightened the protein level of apoptosis-related genes including caspase-3, caspase-8/9, cleaved poly(ADP-ribose) polymerase, and Bid. The fact that LYG-202 had a fitness score similar to that of the casein kinase 2 (CK2) inhibitor naphthyridine-8-carboxylate (CX-4945) implied to us that it may serve as a potential candidate for CK2 inhibitor, and the kinase activity assay suggested that LYG-202 significantly inhibited CK2 activity. Moreover, the electrophoretic mobility shift assay and luciferase assay showed that LYG-202 blocked the TNF-α-induced nuclear factor-κB (NF-κB) survival signaling pathway primarily by inactivating protein kinase CK2. In murine xenograft models, we also found that LYG-202 enhanced TNF-α antineoplastic activity and inhibited CK2 activity and NF-κB-regulated antiapoptotic gene expression. All these results showed that LYG-202 enhanced TNF-α-induced apoptosis by attenuating the CK2-dependent NF-κB pathway and probably is a promising agent in combination with TNF-α.
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Affiliation(s)
- Fei-hong Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
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26
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Hosono K, Yamada E, Endo H, Takahashi H, Inamori M, Hippo Y, Nakagama H, Nakajima A. Increased tumor necrosis factor receptor 1 expression in human colorectal adenomas. World J Gastroenterol 2012; 18:5360-8. [PMID: 23082052 PMCID: PMC3471104 DOI: 10.3748/wjg.v18.i38.5360] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 06/07/2012] [Accepted: 06/15/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the expression statuses of tumor necrosis factor (TNF)-α, its receptors (TNF-R) and downstream effector molecules in human colorectal adenomas.
METHODS: We measured the serum concentrations of TNF-α and its receptors in 62 colorectal adenoma patients and 34 healthy controls. The protein expression of TNF-α, TNF-R1, TNF-R2 and downstream signals of the TNF receptors, such as c-Jun N-terminal kinase (JNK), nuclear factor-κ B and caspase-3, were also investigated in human colorectal adenomas and in normal colorectal mucosal tissues by immunohistochemistry. Immunofluorescence confocal microscopy was used to investigate the consistency of expression of TNF-R1 and phospho-JNK (p-JNK).
RESULTS: The serum levels of soluble TNF-R1 (sTNF-R1) in adenoma patients were significantly higher than in the control group (3.67 ± 0.86 ng/mL vs 1.57 ± 0.72 ng/mL, P < 0.001). Receiver operating characteristic analysis revealed the high diagnostic sensitivity of TNF-R1 measurements (AUC was 0.928) for the diagnosis of adenoma, and the best cut-off level of TNF-R1 was 2.08 ng/mL, with a sensitivity of 93.4% and a specificity of 82.4%. There were no significant differences in the serum levels of TNF-α or sTNF-R2 between the two groups. Immunohistochemistry showed high levels of TNF-R1 and p-JNK expression in the epithelial cells of adenomas. Furthermore, a high incidence of co-localization of TNF-R1 and p-JNK was identified in adenoma tissue.
CONCLUSION: TNF-R1 may be a promising biomarker of colorectal adenoma, and it may also play an important role in the very early stages of colorectal carcinogenesis.
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Testori A, Verhoef C, Kroon HM, Pennacchioli E, Faries MB, Eggermont AM, Thompson JF. Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion. J Surg Oncol 2011; 104:397-404. [DOI: 10.1002/jso.22028] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Narang AS, Varia S. Role of tumor vascular architecture in drug delivery. Adv Drug Deliv Rev 2011; 63:640-58. [PMID: 21514334 DOI: 10.1016/j.addr.2011.04.002] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 03/23/2011] [Accepted: 04/05/2011] [Indexed: 12/14/2022]
Abstract
Tumor targeted drug delivery has the potential to improve cancer care by reducing non-target toxicities and increasing the efficacy of a drug. Tumor targeted delivery of a drug from the systemic circulation, however, requires a thorough understanding of tumor pathophysiology. A growing or receding (under the impact of therapy) tumor represents a dynamic environment with changes in its angiogenic status, cell mass, and extracellular matrix composition. An appreciation of the salient characteristics of tumor vascular architecture and the unique biochemical markers that may be used for targeting drug therapy is important to overcome barriers to tumor drug therapy and to facilitate targeted drug delivery. This review discusses the unique aspects of tumor vascular architecture that need to be overcome or exploited for tumor targeted drug delivery.
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Affiliation(s)
- Ajit S Narang
- Bristol-Myers Squibb, Co., One Squibb Dr., PO Box 191, New Brunswick, NJ 08903-0191, USA.
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29
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Isolated limb perfusion for melanoma in-transit metastases: developments in recent years and the role of tumor necrosis factor alpha. Curr Opin Oncol 2011; 23:183-8. [PMID: 21150602 DOI: 10.1097/cco.0b013e3283424dbc] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The treatment of in-transit metastasis of melanoma remains challenging and is essentially dictated by the biological behavior of melanoma. When lesions are large or numerous, isolated limb perfusion (ILP) is an attractive treatment modality. In this review an overview of literature on treatment options of melanoma in-transit metastases will be discussed. RECENT FINDINGS Most recent studies report on tumor necrosis factor (TNF) and melphalan based ILP (TM-ILP) series or mixed series of TM-ILP and melphalan only based ILP (M-ILP). After TM-ILP complete response rates of 70% (range 44-90%) have been reported, while for M-ILP this is lower with complete response rates of 54% (range 40-76%). The only randomized trial comparing TM-ILP and M-ILP revealed no clear benefit of TNF at 3 months, but improved outcome at 6 months and in patients with bulky disease. Reports on isolated limb infusion (ILI) with melphalan and actinimycin D indicate lower response rates, but similar local control rates as M-ILP at lower cost. SUMMARY ILP is an attractive treatment option in melanoma patients with multiple in-transit metastases. In our opinion TM-ILP is superior to M-ILP as it achieves higher response rates, especially in patients with bulky disease. When lesions are small and in the distal two-thirds of the leg only, ILI is a valuable alternative.
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Corti A, Pastorino F, Curnis F, Arap W, Ponzoni M, Pasqualini R. Targeted Drug Delivery and Penetration Into Solid Tumors. Med Res Rev 2011; 32:1078-91. [DOI: 10.1002/med.20238] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Angelo Corti
- Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience; San Raffaele Scientific Institute; via Olgettina 58, 20132 Milan Italy
| | - Fabio Pastorino
- Experimental Therapy Unit, Laboratory of Oncology; G. Gaslini Children's Hospital; Genoa Italy
| | - Flavio Curnis
- Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience; San Raffaele Scientific Institute; via Olgettina 58, 20132 Milan Italy
| | - Wadih Arap
- David H. Koch Center; The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard; Houston Texas 77030
| | - Mirco Ponzoni
- Experimental Therapy Unit, Laboratory of Oncology; G. Gaslini Children's Hospital; Genoa Italy
| | - Renata Pasqualini
- David H. Koch Center; The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard; Houston Texas 77030
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31
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Pencavel T, Seth R, Hayes A, Melcher A, Pandha H, Vile R, Harrington KJ. Locoregional intravascular viral therapy of cancer: precision guidance for Paris's arrow? Gene Ther 2010; 17:949-60. [PMID: 20445580 DOI: 10.1038/gt.2010.48] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Viral therapy of cancer includes strategies such as viral transduction of tumour cells with 'suicide genes', using viral infection to trigger immune-mediated tumour cell death and using oncolytic viruses for their direct anti-tumour action. However, problems still remain in terms of adequate viral delivery to tumours. A role is also emerging for single-organ isolation and perfusion. Having begun with the advent of isolated limb perfusion for extremity malignancy, experimental systems have been developed for the perfusion of other organs, particularly the liver, kidneys and lungs. These are beginning to be adopted into clinical treatment pathways. The combination of these two modalities is potentially significant. Locoregional perfusion increases the exposure of tumour cells to viral agents. In addition, the avoidance of systemic elimination through the immune and reticulo-endothelial systems should provide a mechanism for increased transduction/infection of target cells. The translation of laboratory research to clinical practice would occur within the context of perfusion programmes, which are already established in the clinic. Many of these programmes include the use of vasoactive cytokines such as tumour necrosis factor-alpha, which may have an effect on viral uptake. Evidence of activation of specific anti-tumour immunological responses by intratumoural and other existing methods of viral administration raises the intriguing possibility of a locoregional therapy, with the ability to affect distant sites of disease. In this review, we examined the state of the literature in this area and summarized current findings before indicating likely areas of continuing interest.
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Affiliation(s)
- T Pencavel
- Targeted Therapy Team, The Institute of Cancer Research, and Sarcoma/Melanoma Unit, Royal Marsden Hospital, London, UK
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32
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Revolutionizing the treatment of locally advanced extremity soft tissue sarcomas: a review on TNFα-based isolated limb perfusion. Eur Surg 2009. [DOI: 10.1007/s10353-009-0479-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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33
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Taeger G, Grabellus F, Taeger G, Grabellus F, Podleska LE, Müller S, Ruchholtz S. Effectiveness of regional chemotherapy with TNF-α/Melphalan in advanced soft tissue sarcoma of the extremities. Int J Hyperthermia 2009; 24:193-203. [DOI: 10.1080/02656730701868387] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Abstract
Tumour necrosis factor (TNF) is a major inflammatory cytokine that was first identified for its ability to induce rapid haemorrhagic necrosis of experimental cancers. When efforts to harness this anti-tumour activity in cancer treatments were underway, a paradoxical tumour-promoting role of TNF became apparent. Now that links between inflammation and cancer are appreciated, is TNF a target or a therapeutic in malignant disease -- or both?
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Affiliation(s)
- Frances Balkwill
- Centre for Cancer and Inflammation, Institute of Cancer, Barts, UK.
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35
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Isolated limb perfusion with TNF-alpha and melphalan in locally advanced soft tissue sarcomas of the extremities. Recent Results Cancer Res 2009; 179:257-70. [PMID: 19230545 DOI: 10.1007/978-3-540-77960-5_16] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Limb-sparing surgery has become all the more important in soft tissue sarcoma (STS) of the extremities since we learned that amputation does not improve survival of these patients. In bulky tumours, however, preoperative strategies to reduce tumour size are then required. Isolated limb perfusion (ILP) with tumour necrosis factor (TNF) has been developed as a biochemotherapeutic therapy to act both on the tumour-associated vasculature and on the tumour itself. It has shown to be a very potent treatment modality, as in early reports response rates were around 80%. Limb salvage could then be achieved in a quite similar percentage. Many confirmatory studies have been performed since, with consistent results even in patients with multiple tumours, after extensive radiotherapy or with metastatic disease, all at the cost of very limited toxicity. This chapter gives an overview of the ILP studies performed in patients with soft tissue limb sarcoma, discusses the mechanism of TNF-mediated vasculotoxic effects on tumour vasculature, and places TNF-based ILP in the multimodality treatment of these patients with extensive STS of the extremities.
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36
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ten Hagen TLM, Seynhaeve ALB, Eggermont AMM. Tumor necrosis factor-mediated interactions between inflammatory response and tumor vascular bed. Immunol Rev 2009; 222:299-315. [PMID: 18364010 DOI: 10.1111/j.1600-065x.2008.00619.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Solid tumor therapy with chemotherapeutics greatly depends on the efficiency with which drugs are delivered to tumor cells. The typical characteristics of the tumor physiology promote but also appose accumulation of blood-borne agents. The leaky tumor vasculature allows easy passage of drugs. However, the disorganized vasculature causes heterogeneous blood flow, and together with the often-elevated interstitial fluid pressure, this state results in poor intratumoral drug levels and failure of treatment. Manipulation of the tumor vasculature could overcome these barriers and promote drug delivery. Targeting the vasculature has several advantages. The endothelial lining is readily accessible and the first to be encountered after systemic injection. Second, endothelial cells tend to be more stable than tumor cells and thus less likely to develop resistance to therapy. Third, targeting the tumor vasculature can have dual effects: (i) manipulation of the vasculature can enhance concomitant chemotherapy, and (ii) subsequent destruction of the vasculature can help to kill the tumor. In particular, tumor necrosis factor alpha is studied. Its action on solid tumors, both directly through tumor cell killing and destruction of the tumor vasculature and indirectly through manipulation of the tumor physiology, is complex. Understanding the mechanism of TNF and agents with comparable action on solid tumors is an important focus to further develop combination immunotherapy strategies.
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Affiliation(s)
- Timo L M ten Hagen
- Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
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37
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Kroon BB, Noorda EM, Vrouenraets BC, van Slooten GW, Nieweg OE. Isolated Limb Perfusion for Melanoma. Surg Oncol Clin N Am 2008; 17:785-94, viii-ix. [DOI: 10.1016/j.soc.2008.04.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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38
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Bellone M, Mondino A, Corti A. Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer. Trends Immunol 2008; 29:235-41. [PMID: 18375183 DOI: 10.1016/j.it.2008.02.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Revised: 01/30/2008] [Accepted: 02/01/2008] [Indexed: 01/08/2023]
Abstract
Chemotherapy has been combined with therapeutic tumor-specific vaccination in an attempt to simultaneously debulk tumors, increase the effector lymphocyte:tumor cell ratio, and favor immune-mediated tumor rejection. However, chemotherapy is often inadequate because of insufficient and uneven drug penetration into tumors, and because it might also cause, in some instances, undesirable side effects and immunosuppression. Here, we suggest a combined approach based on targeted alteration of the endothelial barrier function with vascular disrupting agents, such as tumor necrosis factor-alpha (TNF-alpha), before chemotherapy and tumor-specific vaccination. This approach has the potential to empower chemoimmunotherapeutic strategies by improving cytotoxic drug penetration into tumors while exploiting the proinflammatory and immunostimulating activities of TNF-alpha and active immunotherapy.
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Affiliation(s)
- Matteo Bellone
- Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.
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39
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Verhoef C, de Wilt JHW, Grünhagen DJ, van Geel AN, ten Hagen TLM, Eggermont AMM. Isolated limb perfusion with melphalan and TNF-alpha in the treatment of extremity sarcoma. Curr Treat Options Oncol 2007; 8:417-27. [PMID: 18066703 PMCID: PMC2781100 DOI: 10.1007/s11864-007-0044-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2007] [Accepted: 11/15/2007] [Indexed: 11/29/2022]
Abstract
Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-α) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-α plus melphalan, which resulted in the approval of TNF-α for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-α has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-α-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vasculatory-modulating combination therapy and should be offered in large volume tertiary referral centers.
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Affiliation(s)
- Cornelis Verhoef
- Department of Surgical Oncology, ErasmusMC-Daniel den Hoed Cancer Center, 310 Groene Hilledijk, 3075 EA, Rotterdam, The Netherlands.
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40
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Christopher Windham T, Sondak VK. Soft Tissue Sarcoma. Oncology 2007. [DOI: 10.1007/0-387-31056-8_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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41
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Muret J, Yacoub M, Terrier P, Drusch F, Laplanche A, Gaudin C, Richon C, Le Péchoux C, Le Cesne A, Lejeune FJ, Tursz T, Fouret P, Bonvalot S, Chouaib S. p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-alpha and melphalan. Ann Oncol 2007; 19:793-800. [PMID: 18065405 DOI: 10.1093/annonc/mdm559] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown. PATIENTS AND METHODS We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters. RESULTS P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein. CONCLUSIONS Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.
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Affiliation(s)
- J Muret
- Department of AnesthesiaInstitut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
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42
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Seynhaeve ALB, Hoving S, Schipper D, Vermeulen CE, de Wiel-Ambagtsheer GA, van Tiel ST, Eggermont AMM, Ten Hagen TLM. Tumor necrosis factor alpha mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response. Cancer Res 2007; 67:9455-62. [PMID: 17909055 DOI: 10.1158/0008-5472.can-07-1599] [Citation(s) in RCA: 136] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Successful treatment of solid tumors with chemotherapeutics requires that adequate levels reach the tumor cells. Tumor vascular normalization has been proposed to enhance drug delivery and improve tumor response to chemotherapy. Differently, augmenting leakage of the tumor-associated vasculature, and as such enhance vascular abnormality, may improve tumor response as well. In the present study, we show that addition of low-dose tumor necrosis factor alpha (TNF) to systemic injections with pegylated long circulating liposomes augmented the tumor accumulation of these liposomes 5- to 6-fold, which strongly correlated with enhanced tumor response. Using intravital microscopy, we could study the liposomal distribution inside the tumor in more detail. Especially 100 nm liposomes effectively extravasate in the surrounding tumor tissue in the presence of TNF and this occurred without any effect on tumor vascular density, branching, and diameter. Next to that, we observed in living animals that tumor cells take up the liposomes intact, followed by intracellular degradation. To our knowledge, this is an unprecedented observation. Taken together, TNF renders more tumor vessels permeable, leading to a more homogeneous distribution of the liposomes throughout the tumor, which is crucial for an optimal tumor response. We conclude that delivery of nanoparticulate drug formulations to solid tumor benefits from augmenting the vascular leakage through vascular manipulation with vasoactive drugs like TNF.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/administration & dosage
- Antibiotics, Antineoplastic/pharmacokinetics
- Antibiotics, Antineoplastic/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Doxorubicin/administration & dosage
- Doxorubicin/pharmacokinetics
- Doxorubicin/pharmacology
- Drug Synergism
- Female
- Liposomes/blood
- Liposomes/pharmacokinetics
- Melanoma, Experimental/blood
- Melanoma, Experimental/blood supply
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/metabolism
- Mice
- Mice, Inbred C57BL
- Neovascularization, Pathologic/blood
- Neovascularization, Pathologic/pathology
- Tumor Necrosis Factor-alpha/administration & dosage
- Tumor Necrosis Factor-alpha/pharmacology
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Affiliation(s)
- Ann L B Seynhaeve
- Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands
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43
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Brunstein F, Hoving S, aan de Wiel-Ambagtsheer G, de Bruijn EA, Guetens G, Eggermont AMM, ten Hagen TLM. Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion. Cancer Immunol Immunother 2007; 56:573-80. [PMID: 16896966 PMCID: PMC11030146 DOI: 10.1007/s00262-006-0206-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2006] [Accepted: 05/28/2006] [Indexed: 10/24/2022]
Abstract
Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.
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Affiliation(s)
- Flavia Brunstein
- Department of Surgical Oncology, Erasmus MC, Laboratory of Experimental Surgical Oncology, Daniel den Hoed Cancer Centre, Room Ee 0175, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
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44
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Hoving S, Seynhaeve ALB, van Tiel ST, aan de Wiel-Ambagtsheer G, de Bruijn EA, Eggermont AMM, ten Hagen TLM. Early destruction of tumor vasculature in tumor necrosis factor-alpha-based isolated limb perfusion is responsible for tumor response. Anticancer Drugs 2007; 17:949-59. [PMID: 16940805 DOI: 10.1097/01.cad.0000224450.54447.b3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-alpha in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-alpha plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.
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Affiliation(s)
- Saske Hoving
- Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 3000 DR Rotterdam, The Netherlands
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45
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Farma JM, Puhlmann M, Soriano PA, Cox D, Paciotti GF, Tamarkin L, Alexander HR. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor. Int J Cancer 2007; 120:2474-80. [PMID: 17330231 DOI: 10.1002/ijc.22270] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.
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Affiliation(s)
- Jeffrey M Farma
- Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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46
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van Horssen R, Ten Hagen TLM, Eggermont AMM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist 2006; 11:397-408. [PMID: 16614236 DOI: 10.1634/theoncologist.11-4-397] [Citation(s) in RCA: 537] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Tumor necrosis factor alpha (TNF-alpha), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. Although named for its antitumor properties, TNF has been implicated in a wide spectrum of other diseases. The current use of TNF in cancer is in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas and other irresectable tumors of any histology to avoid amputation of the limb. It has been demonstrated in the isolated limb perfusion setting that TNF-alpha acts synergistically with cytostatic drugs. The interaction of TNF-alpha with TNF receptor 1 and receptor 2 (TNFR-1, TNFR-2) activates several signal transduction pathways, leading to the diverse functions of TNF-alpha. The signaling molecules of TNFR-1 have been elucidated quite well, but regulation of the signaling remains unclear. Besides these molecular insights, laboratory experiments in the past decade have shed light upon TNF-alpha action during tumor treatment. Besides extravasation of erythrocytes and lymphocytes, leading to hemorrhagic necrosis, TNF-alpha targets the tumor-associated vasculature (TAV) by inducing hyperpermeability and destruction of the vascular lining. This results in an immediate effect of selective accumulation of cytostatic drugs inside the tumor and a late effect of destruction of the tumor vasculature. In this review, covering TNF-alpha from the molecule to the clinic, we provide an overview of the use of TNF-alpha in cancer starting with molecular insights into TNFR-1 signaling and cellular mechanisms of the antitumor activities of TNF-alpha and ending with clinical response. In addition, possible factors modulating TNF-alpha actions are discussed.
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Affiliation(s)
- Remco van Horssen
- Department of Surgical Oncology, Erasmus MC--Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
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Noorda EM, Vrouenraets BC, Nieweg OE, Kroon BBR. Isolated limb perfusion in regional melanoma. Surg Oncol Clin N Am 2006; 15:373-84. [PMID: 16632221 DOI: 10.1016/j.soc.2005.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Adjuvant perfusion to excision of a primary melanoma cannot be recommended because of its limited effect. In patients who have frequently recur-ring resectable locoregional melanoma, perfusion may provide valuable loco-regional disease control by decreasing the number of recurrences and lesions per recurrence. Randomized studies are needed to further establish the role of perfusion as an adjuvant treatment for resectable recurrences of melanoma. Unresectable limb melanoma is the primary indication for perfusion. Better response rates tend to be seen when TNF-a is used in patients who have a high tumor load. Repeat perfusion is feasible, resulting in response rates similar to those of a first perfusion for locoregional melanoma. Older age itself is not a contraindication for perfusion. The long-term health-related quality of life of survivors of melanoma who underwent treatment with perfusion is comparable to that of their healthy peers in the general Dutch population.
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Affiliation(s)
- Eva M Noorda
- Department of Surgery, Slotervaart Hospital, Louwesweg 6, Amsterdam 100 BK, the Netherlands.
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Hoving S, Seynhaeve ALB, van Tiel ST, Eggermont AMM, ten Hagen TLM. Addition of low-dose tumor necrosis factor-alpha to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats. Anticancer Drugs 2006; 16:667-74. [PMID: 15930896 DOI: 10.1097/00001813-200507000-00012] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Improved efficacy of Doxil (STEALTH liposomal doxorubicin) compared to free doxorubicin has been demonstrated in the treatment of several tumor types. We have shown that addition of low-dose tumor necrosis factor (TNF) to systemic Doxil administration dramatically improved tumor response in the highly vascularized rat soft tissue sarcoma BN175. Whether a similar enhanced efficacy can be achieved in less vascularized tumors is uncertain. We therefore examined the effect of systemic administration of Doxil in combination with low-dose TNF in intermediate vascularized osteosarcoma-bearing rats (ROS-1). Small fragments of the osteosarcoma were implanted s.c. in the lower limb. Treatment was started when the tumors reached an average diameter of 1 cm. Rats were treated with five i.v. injections at 4-day intervals with Doxil or doxorubicin and TNF. Systemic treatment with Doxil resulted in a better tumor growth delay than free doxorubicin, but with progressive diseases in all animals. The 3.5-fold augmented accumulation of Doxil compared to free doxorubicin presumably explains the enhanced tumor regression. Addition of low-dose TNF augmented the anti-tumor activity of Doxil, although no increased drug uptake was found compared to Doxil alone. In vitro studies showed that ROS-1 is sensitive to TNF, but systemic treatment with TNF alone did not result in a tumor growth delay. Furthermore, we demonstrated that treatment with Doxil alone or with TNF resulted in massive coagulative necrosis of tumor tissue. In conclusion, combination therapy of Doxil and low-dose TNF seems attractive for the treatment of highly vascularized tumors, but also of intermediate vascularized tumors like the osteosarcoma.
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Affiliation(s)
- Saske Hoving
- Department of Surgical Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
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Calfa CI, Rosenblatt JD, Cho HM, Webster K, Shin SU. Antibodies and antibody-fusion proteins as anti-angiogenic, anti-tumor agents. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.uct.2006.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Grünhagen DJ, de Wilt JHW, ten Hagen TLM, Eggermont AMM. Technology insight: Utility of TNF-alpha-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities. ACTA ACUST UNITED AC 2006; 3:94-103. [PMID: 16462850 DOI: 10.1038/ncponc0426] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2005] [Accepted: 12/14/2005] [Indexed: 01/12/2023]
Abstract
Isolated limb perfusion (ILP) with melphalan is effective in the treatment of small multiple melanoma intransit metastases and is utilized widely for this indication. The treatment is much less effective against bulky melanoma metastases and has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor-necrosis factor-alpha (TNF-alpha) to this treatment approach has changed the situation dramatically. High response rates and limb-salvage rates have been reported in multicenter trials that combined ILP with TNF-alpha plus melphalan; these trials resulted in the approval of TNF-alpha for bulky melanoma metastases and soft tissue sarcomas in Europe in 1998. Subsequently, many doctors working in European centers have been trained, and a series of confirmatory reports from single institutions have now been published regarding the efficacy of the procedure. TNF-alpha has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion, and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in bulky tumors, soft tissue sarcomas, bulky melanomas, and various other tumor types. This induction therapy therefore allows tumor remnants to be resected some 3 months after ILP thus avoiding limb amputation. TNF-alpha-based ILP is a well-established treatment that aims to avoid amputations regardless of the tumor size and type. It represents an important example of combination therapy that modulates the tumor vasculature and should be offered in high-volume tertiary referral centers.
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Affiliation(s)
- Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
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