Effects of BMY 25282, a mitomycin C analogue, in mitomycin C-resistant human colon cancer cells.
BMY 25282, a newly designed analogue of mitomycin C (MMC), was assessed for its non-cross-resistant cytotoxic and biochemical action against MMC-resistant human colon carcinoma cells. The analogue has an amidine substituted at position 7 of MMC and has a more efficient intracellular activation to its active species than MMC. In this study we demonstrated that BMY 25282 can overcome MMC resistance in a series of previously described human colon carcinoma cells resistant to MMC (Cancer Res., 44: 5880, 1984). The non-cross-resistance of the analogue in the model was confirmed in vivo by treating tumor xenograft-bearing athymic mice with equitoxic doses of MMC or BMY 25282. We further investigated the formation of interstrand DNA cross-link (IDC) formation by BMY 25282 and MMC. MMC-sensitive cells contained 3 to 8 times as many IDCs as resistant colon carcinoma cells, while no significant differences in IDCs were found between the MMC-sensitive or -resistant cells incubated with BMY 25282. When MMC-sensitive or -resistant cells were exposed to the 70% inhibition concentration of either MMC or BMY 25282, no differences were seen with respect to IDC formation. These studies demonstrate that BMY 25282 is able to overcome MMC resistance in a series of human colon carcinoma cells and that IDC formation in the MMC-sensitive or -resistant cells parallels cytotoxicity for both MMC and the analogue.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D051381:Rats; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D008937:Mitomycins; D016685:Mitomycin; C046941:N(6)-((dimethylamino)methylene)mitomycin C; D004247:DNA