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

H. Xia, R. J. Bleicher, X. Hu, S. K. Srivastava, V. Gupta, Howard A. Zaren, S. V. Singh

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1 Scopus citations

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 The BMS-181174-resistant variant (J82/BMS) was established by repealed continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months.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. 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.

Original languageEnglish (US)
Pages (from-to)461-466
Number of pages6
JournalBritish Journal of Cancer
Volume76
Issue number4
DOIs
StatePublished - Jan 1 1997

Keywords

  • Bladder cancer
  • Mitomycin C
  • Mitomycin C analogue
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Xia, H., Bleicher, R. J., Hu, X., Srivastava, S. K., Gupta, V., Zaren, H. A., & Singh, S. V. (1997). Characterization of a BMS-181174-resistant human bladder cancer cell line. British Journal of Cancer, 76(4), 461-466. https://doi.org/10.1038/bjc.1997.410