Characterization of a BMS-181174-resistant human bladder cancer cell line.
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.
Xia
H
H
Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pennsylvania 15219, USA.
Bleicher
R J
RJ
Hu
X
X
Srivastava
S K
SK
Gupta
V
V
Zaren
H A
HA
Singh
S V
SV
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008937:Mitomycins; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C