W-7, a calmodulin inhibitor, potentiates dacarbazine cytotoxicity in human neoplastic cells.
Dacarbazine induces damage in replicative DNA, with a maximum level at 24 hr after treatment. Repair of these lesions does not occur when cells are post-treated with the calmodulin inhibitor W-7. In parallel cell cytotoxicity increases. The augmentation effect of W-7 is prevented by simultaneous incubation of cells with high levels of calmodulin and does not occur in cells pre-treated with aphidicolin (to stop DNA synthesis). Furthermore, W-5, an analogue of W-7 with a less inhibitory effect on calmodulin, does not interfere with DNA repair. The results show that calmodulin and/or calmodulin-regulated proteins are involved in the repair process of dacarbazine-induced DNA lesions.
D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000187:drug effects; D003606:Dacarbazine / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*
D002147:Calmodulin; D004273:DNA, Neoplasm; D013449:Sulfonamides; C017967:W 7; D003606:Dacarbazine