Tumor Necrosis Factor: Renaissance as a Cancer Therapeutic?

Daniel, Dylan; Ns, Wilson

doi:10.2174/156800908783769346

Cited by 56 publications

(45 citation statements)

References 144 publications

(177 reference statements)

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“…Production of TNF-α by OSCC cells could result in resistance to the cytotoxic action of host derived TNF-α or exogenous recombinant TNF-α administered in a therapeutic setting. TNF-α has been used in several clinical trials in cancer patients and has resulted in no significant improvements in survival (Sherman et al, 1988;Daniel et al, 2008). Local production by tumor cells and their consequent resistance may in part explain these disappointing results.…”

Section: Discussionmentioning

confidence: 99%

Association of Serum and Salivary Tumor Necrosis Factor-α with Histological Grading in Oral Cancer and its Role in Differentiating Premalignant and Malignant Oral Disease

Rajkumar

Dineshkumar²,

Padmanaban³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Oral squamous cell carcinoma (OSCC) is an important malignancy throughout the world; early detection is an important criterion for achieving high cure rate. Out of the many reported markers for OSCC, this study validated the efficacy of tumor necrosis factor-α (TNF-α) in differentially diagnosing premalignant oral lesions and OSCC. Also, the study aimed to correlate the levels of salivary and serum TNF-α with clinicopathologic factors. Materials and Methods: A prospective experimental laboratory study was designed. Serum and salivary samples from 100 subjects in each group of healthy control, premalignant disease (PMD) and OSCC were collected for the study following appropriate exclusion and inclusion criteria. Serum and salivary level of TNF-α was analysed by enzyme linked immunosorbent assay. The data obtained were subjected to appropriate statistical analysis. Results: Increased level of both serum and salivary TNF-α was observed in OSCC subjects compared to healthy control and PMD group. Receiver operator characteristic curve analysis and area under curve values showed high specificity and sensitivity for salivary TNF-α in differentiating OSCC from PMD and healthy controls. There was significant increase in TNF-α level in moderately and poorly differentiated lesion compared to well differentiated lesion and in stage IV of clinical stage. A positive correlation was observed only with histological grading of OSCC and TNF-α. Conclusions: Salivary TNF-α is proved to be superior for detecting OSCC. Increase in TNF-α with histological grading and clinical staging suggests a role in prognosis.

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Section: Discussionmentioning

confidence: 99%

Association of Serum and Salivary Tumor Necrosis Factor-α with Histological Grading in Oral Cancer and its Role in Differentiating Premalignant and Malignant Oral Disease

Rajkumar

Dineshkumar²,

Padmanaban³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…TNF-a has demonstrated potent antitumor activity in animal models. 36 Despite some observed toxicity in preclinical models, its potent activity against human tumor xenografts led to clinical trials in humans. However, the results were a small number of minimal responses with extensive hemodynamic side effects and hepatic toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…However, the results were a small number of minimal responses with extensive hemodynamic side effects and hepatic toxicity. 36 Those trial results were sufficiently disappointing that studies of systemically delivered, single-agent TNF-a were discontinued. To avoid systemic toxicity, currently, TNF-a is used clinically only in isolated organ perfusion for human melanoma and soft tissue sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Tandle

Hanna

Lorang

et al. 2008

Cancer

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BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor‐α (TNF‐α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF‐α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF‐α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno‐associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF‐α (AAVP‐TNF‐α). The activity of AAVP‐TNF‐α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP‐TNF‐α infection of human melanoma cells resulted in high levels of TNF‐α expression. Systemic administration of targeted AAVP‐TNF‐α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF‐α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF‐α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF‐α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy. Cancer 2009. Published 2008 by the American Cancer Society.

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“…These receptors are characterized by a death domain in the cytoplasmic tail which transduces signals from their cognate ligands such as TNFα, Fas ligand (FasL) and TNF-related apoptosis inducing ligand (TRAIL). Despite disappointing results from early clinical trials for recombinant TNFα, which showed severe toxicity after systemic exposure (5,6), there is a continued effort to separate the unwanted toxicities from its potent apoptosis inducing activity by modifying TNF protein; for example, NGR-TNFα fusion protein (7) and TNFα-colloidal gold nanoparticles (8) are currently in clinical trails for treating human cancers.…”

Section: Introductionmentioning

confidence: 99%

Mislocalization of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells

et al. 2012

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ABSTRACT:Multiple clinical trials are ongoing to evaluate the potential antitumor activity of human TNF variants, Fas ligand (FasL), TNF-related apoptosis inducing ligand (TRAIL) and its agonistic antibodies. These drug products act through the death receptors (DRs) TNF receptor 1 (TNFR1), Fas/CD95, DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2), respectively. Therefore, characterization of the level and localization of DR expression in cancer cells is important for DR-targeted therapy. In this study, we examined the subcellular distribution of the four DRs in a panel of 10 human breast cancer cell lines by western blots and flow cytometry and 50 human breast tumors by immunohistochemistry. Despite their total protein expressions, the DRs were found to be absent on the surface of some cell lines. Consistent with this result, all four DRs were found to be mostly expressed in the cytoplasm and/or the nucleus of primary breast tumors (n=50). We further determined the growth inhibition activity (GI50) of the death ligands, recombinant human TNFα, FasL and TRAIL, and found a correlation with the subcellular localization of the corresponding DRs. These results demonstrate an aberrant expression of the death receptors in breast cancer cells, and suggest that the lack of surface DRs appears to be predictive of tumor resistance to DR-targeted therapies.

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Tumor Necrosis Factor: Renaissance as a Cancer Therapeutic?

Cited by 56 publications

References 144 publications

Association of Serum and Salivary Tumor Necrosis Factor-α with Histological Grading in Oral Cancer and its Role in Differentiating Premalignant and Malignant Oral Disease

Association of Serum and Salivary Tumor Necrosis Factor-α with Histological Grading in Oral Cancer and its Role in Differentiating Premalignant and Malignant Oral Disease

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Mislocalization of death receptors correlates with cellular resistance to their cognate ligands in human breast cancer cells

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