Targeting calmodulin for the development of novel cancer chemotherapeutic agents.
The calcium-messenger system is involved in the regulation of cellular proliferation. Alterations in any of the components of this system could lead to states of abnormal cellular proliferation. We have focused our attention on drugs that antagonize the actions of calmodulin, a central calcium regulatory protein. Following purification of calmodulin from normal and malignant cells by preparative polyacrylamide gel electrophoresis, we determined the sensitivity of the molecule to several classes of calmodulin antagonists and found a direct correlation between antagonism of calmodulin and inhibition of cellular viability. Fluphenazine mustard was shown to be an irreversible calmodulin antagonist and an extremely potent inhibitor of leukemic cell growth. Dequalinium and rhodamine-123, drugs selectively accumulated in malignant cells, were found to be potent calmodulin antagonists, and inhibited the growth of C6 astrocytoma cells. Further studies led to the observation that the combination of calmodulin antagonists with bleomycin produced synergistic cell-kill that was related to enhanced DNA damage. The combination of trifluoperazine and bleomycin was safely administered to 19 heavily pre-treated cancer patients, of whom four had excellent clinical responses. These studies suggest that calmodulin might be an important target for the development of new antineoplastic drugs.
Hait
W N
WN
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D002455:Cell Division; D004249:DNA Damage; D006801:Humans
D000970:Antineoplastic Agents; D002147:Calmodulin