Characterization of a human bladder cancer cell line selected for resistance to BMY 25067, a novel analogue of mitomycin C.

Abstract

This study describes characteristics of a human bladder cancer cell line, SCaBER/R, selected for resistance to a mitomycin C (MMC) analogue BMY 25067. The SCaBER/R cell line was isolated by repeated 24 h exposures of the parental cells to 0.09 microM BMY 25067 (IC90, 24 h drug exposure) over a period of about 180 days. Approximately 2.2-fold higher concentration of BMY 25067 was required to kill 50% of the SCaBER/R cell line compared with parental cells (p < 0.001). The IC20 and IC90 values for BMY 25067 were also significantly higher in the SCaBER/R cell line than in SCaBER. Unlike most MMC resistant cell lines, the SCaBER/R cell line displayed a marked cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and lacked cross-resistance to cisplatin, doxorubicin or VP-16. The SCaBER/R cell line also displayed a marked cross-resistance to the parent drug (MMC) and BMY 25282, another analogue of MMC. NADPH cytochrome P450 reductase activity, an enzyme implicated in bio-reductive activation of MMC, did not differ significantly in these cells. DT-diaphorase activity, another MMC activation enzyme, was significantly lower in the SCaBER/R cell line when compared to the SCaBER cells. These results suggest that relatively lower sensitivity of SCaBER/R cell line to MMC and BMY 25067 may result from impaired drug activation. Cellular levels of glutathione (GSH) and GSH-transferase (GST), which have been suggested to affect the cytotoxicity of MMC, were comparable in SCaBER and SCaBER/R cell lines. BMY 25067 induced DNA interstrand cross-links (DNA-ISC) could not be detected in either of the cell lines even at drug concentrations which produced a significant cell kill. These findings suggest that (a) cellular resistance to BMY 25067 in the SCaBER/R cell line may be due to impaired drug activation, and (b) the nature of the cytotoxic produced by BMY 25067 may be different from that of MMC.

• Authors: S V Singh, B H Xu, V Gupta, E O Emerson, H A Zaren, J P Jani
• Journal: Cancer letters (Cancer Lett) Vol. 95 Issue 1-2 Pg. 49-56 (Aug 16 1995) ISSN: 0304-3835 [Print] Ireland
• PMID: 7656243 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Mitomycins
• Mitomycin
• N-7-(2-(nitrophenyldithio)ethyl)mitomycin C
• NADPH-Ferrihemoprotein Reductase
• NAD(P)H Dehydrogenase (Quinone)
• Glutathione Transferase
• Glutathione

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle
• Drug Resistance
• Glutathione (metabolism)
• Glutathione Transferase (metabolism)
• Humans
• In Vitro Techniques
• Mitomycin (pharmacology)
• Mitomycins
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• NADPH-Ferrihemoprotein Reductase (metabolism)
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms (pathology)