Modulation of doxorubicin-induced chromosomal damage by calmodulin inhibitors and its relationship to cytotoxicity in progressively doxorubicin-resistant tumor cells

Modulation of doxorubicin (DOX) cytotoxicity by the calmodulin inhibitor trifluoperazine (TFP) in progressively doxorubicin-resistant L1210 mouse leukemia cells is unrelated to effects on drug accumulation. Based on the clastogenic activity of DOX, the effects of TFP and the selective calmodulin inhibitor 1,3-dihydro-1-[1-[4-methyl-4H,6H-pyrrolo[1,2-a][4,1]- benzoxazepin-4-yl-methyl]-4-piperidinyl]-2H-benzimidazol-2-o ne(1:1) maleate (CGS9343B) on DOX-induced chromosomal damage and its relationship to cytotoxicity were evaluated in sensitive and progressively DOX-resistant L1210 cells. Potentiation of DOX cytotoxicity by CGS9343B (a potent inhibitor of calmodulin which does not inhibit protein kinase C) was related to the level of resistance. Further, for equivalent cytotoxicity, cellular DOX levels in the absence versus the presence of TFP or CGS9343B were markedly higher. Exposure to calmodulin inhibitors following DOX treatment enhanced chromosomal aberrations and cytotoxicity. Maximal effects of calmodulin inhibitors were apparent when used during and after DOX treatment, and potentiation of cytotoxicity was related to modulation of DOX-induced chromosomal aberrations. Results suggest that inhibition of calmodulin-regulated processes is a potential target in the modulation of DNA damage/repair, and could play a pivotal role in the expression of "acquired resistance" to DOX.