Hait W N
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Anticancer Drug Des. 1987 Oct;2(2):139-49.
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.
钙信使系统参与细胞增殖的调节。该系统任何一个组成部分的改变都可能导致细胞异常增殖状态。我们将注意力集中在拮抗钙调蛋白（一种核心钙调节蛋白）作用的药物上。通过制备性聚丙烯酰胺凝胶电泳从正常细胞和恶性细胞中纯化钙调蛋白后，我们测定了该分子对几类钙调蛋白拮抗剂的敏感性，发现钙调蛋白的拮抗作用与细胞活力的抑制之间存在直接关联。氟奋乃静氮芥被证明是一种不可逆的钙调蛋白拮抗剂，也是白血病细胞生长的极强抑制剂。地喹氯铵和罗丹明 - 123这两种选择性积聚在恶性细胞中的药物，被发现是有效的钙调蛋白拮抗剂，并能抑制C6星形细胞瘤细胞的生长。进一步的研究发现，钙调蛋白拮抗剂与博来霉素联合使用会产生协同细胞杀伤作用，这与增强的DNA损伤有关。三氟拉嗪和博来霉素的联合用药已安全应用于19例经过大量预处理的癌症患者，其中4例有良好的临床反应。这些研究表明，钙调蛋白可能是开发新型抗肿瘤药物的重要靶点。
