Beck W T
Adv Enzyme Regul. 1984;22:207-27. doi: 10.1016/0065-2571(84)90015-3.
Vinca alkaloid-resistant human leukemic cells express the multiple drug-resistant phenotype, characterized by cross resistance to natural product compounds of unrelated structure and action. While there are also distinct biochemical lesions associated with this phenotype, their role(s) in the expressions of resistance is not known at this time. More clear, however, is our understanding of the pharmacologic determinants of this resistance--apparent decreased drug uptake and decreased drug retention. This latter phenomenon has been attributed to the workings of an active efflux pump, but data presented here and elsewhere permit an alternative explanation--that of altered drug binding to an as yet unidentified target(s). Elucidation of the mechanism of multiple drug resistance is important in the design of new chemotherapeutic strategies to overcome it. In this regard, calcium channel blocking agents and calmodulin inhibitors can cause an apparent reversal of resistance by enhancing the cytotoxic effectiveness of the anticancer drugs, possibly by increasing the amount of drug retained by the tumor cells. The basis for this enhanced retention and cytotoxicity is not presently known, but it may be related to cellular calcium fluxes, calmodulin content or membrane fluidity and permeability. The meaning of these findings is unclear at the present time, but they may provide new insights into the mechanism of action and ultimate cellular target(s) for Vinca alkaloids. Whether these modifying drugs sensitize the cells to the action of the alkaloids or potentiate the oncolytic drug effect in the cell remains to be determined. Regardless of the mechanism, calcium channel blocking agents may have a role in the combination chemotherapy of the leukemias with Vinca alkaloids.
长春花生物碱耐药的人白血病细胞表现出多药耐药表型，其特征是对结构和作用不相关的天然产物化合物产生交叉耐药。虽然也有与这种表型相关的明显生化损伤，但目前尚不清楚它们在耐药表达中的作用。然而，我们对这种耐药的药理学决定因素有了更清晰的认识——明显的药物摄取减少和药物滞留减少。后一种现象被归因于活性外排泵的作用，但此处和其他地方提供的数据允许另一种解释——药物与尚未确定的靶点结合改变。阐明多药耐药机制对于设计克服它的新化疗策略很重要。在这方面，钙通道阻滞剂和钙调蛋白抑制剂可通过增强抗癌药物的细胞毒性效力，可能通过增加肿瘤细胞保留的药物量，导致耐药的明显逆转。这种增强的滞留和细胞毒性的基础目前尚不清楚，但可能与细胞钙通量、钙调蛋白含量或膜流动性和通透性有关。目前这些发现的意义尚不清楚，但它们可能为长春花生物碱的作用机制和最终细胞靶点提供新的见解。这些修饰药物是使细胞对生物碱的作用敏感，还是增强细胞内溶瘤药物的作用，仍有待确定。无论机制如何，钙通道阻滞剂可能在白血病与长春花生物碱的联合化疗中发挥作用。
