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Anti-tumor action of tumor necrosis factor against Bomirski Ab melanoma in hamsters.

ABSTRACT: Tumor necrosis factor (TNF) is a cytokine able to exert anti-tumor activity in various models and modes of applications. However, the exact mechanism mediating the in vivo anti-tumor effect of TNF has not yet been clarified.The effects of intratumoral injection of rat TNF into hamsters bearing Bomirski Ab amelanotic melanoma, a fast growing tumor of high metastatic potential, were tested. Subcutaneous injections of the anti-angiogenic compound TNP-470 allowed analysis of its influence on the effects of TNF administration.TNF application resulted in a significant inhibition of tumor growth and changes in metastasis pattern. Accelerated hemorrhagic necrosis was also observed, indicating the effect of the cytokine on tumor vessels. Moreover, the synergistic anti-tumor effect of TNF and anti-angiogenic agent TNP-470 suggested a cooperative activity of both substances on tumor vasculature. Microscopically, the effect of TNF injections was expressed by an increase in the amount of tumor cells with nuclear pyknosis and karryorrhexis. In vitro assays indicated a direct cytotoxic effect of TNF against Ab melanoma cells, most probably as an outcome of apoptosis. Intratumoral application of TNF also caused some modulation of cytokine response in melanoma-bearing hamsters as evidenced by increased levels of IL-6 in blood serum.This study established Bomirski Ab melanoma as a useful model for complex analysis of the anti-tumor activity of TNF.

SUBMITTER: Koszalka P

PROVIDER: S-EPMC2766459 | biostudies-other | 2007 Jul-Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundOne-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-? (TNF-?).MethodsMice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-?, were tested for their effects on breast cancer cell proliferation.ResultsWe produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-?, antibodies acted synergistically on SK-BR-3 cells, but antagonistically on BT-474 cells. A representative anti-HER2 antibody inhibited Akt and ERK1/2 phosphorylation leading to cyclin D1 accumulation and growth arrest in SK-BR-3 cells, independently from TNF-?.ConclusionsNovel antibodies against extracellular domain of HER2 may serve as potent anti-cancer bioactive molecules. Cell-dependent synergy and antagonism between anti-HER2 antibodies and TNF-? provide evidence for a complex interplay between HER2 and TNF-? signaling pathways. Such complexity may drastically affect the outcome of HER2-directed therapeutic interventions.

Project description:To investigate genetic factors that might help define which Crohn's disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

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Anti-tumor action of tumor necrosis factor against Bomirski Ab melanoma in hamsters.

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