Characterization of a BMS-181174-resistant human bladder cancer cell line.

Abstract

This study was undertaken to elucidate the mechanism of cellular resistance to BMS-181174, a novel analogue of mitomycin C (MMC), in a human bladder cancer cell line. The BMS-181174-resistant variant (J82/BMS) was established by repeated continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months. A 2.6-fold higher concentration of BMS-181174 was required to kill 50% of J82/BMS cell line compared with J82. The J82/BMS cell line exhibited collateral sensitivity to 5-fluorouracil (5-FU), but was significantly more cross-resistant to MMC, melphalan, taxol, doxorubicin and VP-16. NADPH cytochrome P450 reductase and DT-diaphorase activities, which have been implicated in bioreductive activation of MMC, were significantly lower in the J82/BMS cell line than in J82. The cytotoxicity of BMS-181174, however, was not affected in either cell line by pretreatment with dicoumarol, which is an inhibitor of DT-diaphorase activity. These results argue against a role of DT-diaphorase in cellular bioactivation of BMS-181174, a conclusion consistent with that of Rockwell et al (Biochem Pharmacol, 50: 1239-1243, 1995). BMS-181174-induced DNA interstrand cross-link (DNA-ISC) frequency was markedly lower in J82/BMS cell line than in J82 at every drug concentration tested. The results of the present study suggest that cellular resistance to BMS-181174 in J82/BMS cell line may be due to reduced DNA-ISC formation. However, the mechanism of relatively lower BMS-181174 induced DNA-ISC formation in J82/BMS cell line than in parental cells remains to be clarified.

• Authors: H Xia, R J Bleicher, X Hu, S K Srivastava, V Gupta, H A Zaren, S V Singh
• Journal: British journal of cancer (Br J Cancer) Vol. 76 Issue 4 Pg. 461-6 ( 1997) ISSN: 0007-0920 [Print] England
• PMID: 9275022 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• Mitomycins
• Mitomycin
• N-7-(2-(nitrophenyldithio)ethyl)mitomycin C

Topics

• Antineoplastic Agents, Alkylating (pharmacology)
• Cell Survival (drug effects)
• Drug Resistance
• Humans
• Mitomycin (pharmacology)
• Mitomycins
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms (drug therapy, pathology)