LICHT, T and LUBBERT, M and MARTENS, C and BROSS, KJ and FIEBIG, HH and MERTELSMANN, R and HERRMANN, F (1995) MODULATION OF VINDESINE AND DOXORUBICIN RESISTANCE IN MULTIDRUG-RESISTANT PLEURAL MESOTHELIOMA CELLS BY TUMOR-NECROSIS-FACTOR-ALPHA. CYTOKINES AND MOLECULAR THERAPY, 1 (2). pp. 123-132. ISSN 1355-6568,
Full text not available from this repository.Abstract
Tumor necrosis factor-alpha (TNF-alpha) has been shown to enhance the cytotoxicity of a variety of antineoplastic agents. To examine whether multidrug-resistant cells are targets of TNF-alpha, and whether TNF-alpha is capable of modulating chemoresistance of these cells, a pleural mesothelioma cell line (PXF1118L) and two multidrug-resistant sublines thereof were used as experimental models. Drug resistance of these cells was due to P-glycoprotein expression, as confirmed by (1) staining with a monoclonal antibody (MRK16) specific for human P-glycoprotein, (2) decreased accumulation of [H-3]vinblastine that was reversed by verapamil, and (3) enhanced cytotoxicity of vindesine in the presence of verapamil. Parental and multidrug-resistant cells exhibited little but comparable sensitivity to TNF-alpha alone. Combining TNF-alpha with vindesine or, to a lesser extent, with doxorubicin, but not with cisplatin, resulted in greater cytotoxicity towards multidrug-resistant cells than seen for each compound alone, indicating a synergism. In contrast, TNF-alpha failed to modulate vindesine or doxorubicin cytotoxicity in parental cells. [H-3]Vinblastine accumulation was unaffected by TNF-alpha, and chemoresistance was reduced by TNF-alpha also in the presence of verapamil (10 mu M), indicating that TNF-alpha was acting in a way different from calcium-channel blockers. Though the molecular mechanism by which TNF-alpha was enhancing vindesine and doxorubicin cytotoxicity remained undefined in this study, the numbers of TNF-alpha binding sites on parental and on multidrug-resistant cells were similar, and P-glycoprotein expression was unmodulated during the entire 48 h incubation period. In conclusion, we show that TNF-alpha increases the cytotoxicity of anticancer drugs in multidrug-resistant tumor cells by a mechanism that differs from most chemosensitizing agents, including verapamil. Further studies will be needed to clarify the mechanism by which TNF-alpha synergizes with anticancer drugs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DRUG-RESISTANCE; P-GLYCOPROTEIN; BONE-MARROW; CHEMOTHERAPY; LEUKEMIA; ACCUMULATION; TRANSPORTER; EXPRESSION; VERAPAMIL; TOXICITY; CHEMOTHERAPY; CHEMOSENSITIZING AGENTS; CYTOKINES; MDR1 GENE; P-GLYCOPROTEIN |
| Depositing User: | Dr. Gernot Deinzer |
| Last Modified: | 19 Oct 2022 08:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/52495 |
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