Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line.
9-fold more resistant to mitomycin C (MMC) than parental cells (J82/WT). The IC(50) values for paclitaxel in J82/WT and J82/MMC-2 cell lines were 0.7+/-0.03 and 2.8+/-0.7 microM, respectively (P<0. 05). Thus, the J82/MMC-2 cell line exhibited 4-fold cross-resistance to paclitaxel compared with J82/WT. Intracellular accumulation of [(3)H]paclitaxel was comparable in J82/WT and J82/MMC-2 cell lines. There were no qualitative or quantitative differences between the J82/WT and J82/MMC-2 cell lines in terms of their alpha-tubulin and beta-tubulin contents. Paclitaxel-induced apoptosis could not be detected in either cell line over a wide range of drug concentrations. These results indicate that cross-resistance to paclitaxel in the J82/MMC-2 cell line is not linked to reduced drug accumulation, increased drug efflux, alterations in tubulin content or reduced paclitaxel-induced apoptosis. Paclitaxel-induced DNA strand breakage, however, determined by alkaline elution, was markedly lower in the J82/MMC-2 cell line than in J82/WT. These results suggest that paclitaxel cross-resistance in J82/MMC-2 may be attributed to reduced paclitaxel-induced DNA strand breakage. The precise mechanism of reduced paclitaxel-induced DNA strand breakage in J82/MMC-2 cell line relative to J82/WT cells, however, remains to be elucidated.
Bleicher
R J
RJ
Department of Surgery, Mercy Hospital of Pittsburgh, PA 15219, USA. bleicher@icubed.com
Xia
H
H
Zaren
H A
HA
Singh
S V
SV
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D016685:Mitomycin; D017239:Paclitaxel