Tsuruo T
Prog Clin Biol Res. 1986;223:203-16.
Innate drug resistance as well as acquired multidrug resistance are directly related to ineffectiveness and failure of the cancer chemotherapy. The mechanisms of such resistance, especially those of innate resistance, have not been fully elucidated. We have established vincristine (VCR)- and Adriamycin (ADM)-resistant sublines of human myelogenous leukemia K562 by continuous drug exposure. These resistant sublines contained double minute chromosomes and express a glycoprotein with a 180,000 dalton M.W. Analysis of VCR and ADM sensitivities of several isolated clones from these resistant sublines revealed a tight relationship between these two resistant mechanisms. However, ADM resistant sublines are always highly resistant to VCR, but VCR resistant sublines are not necessarily highly resistant to ADM, suggesting the presence different mechanisms of ADM and VCR resistance. Calcium channel blockers inhibit the drug efflux in these resistant tumor cells, thereby overcoming of drug resistance. Greater potentition was observed with antitumor agents to which VCR- and ADM-resistant cells were highly cross-resistant. Calcium channel blockers always show higher potentiation with VCR than ADM, and the clones with greater resistance to VCR generally accumulated less VCR and generally possessed a higher rate of VCR efflux. These results might indicate that a major mechanism of VCR resistance could be a defficiency in drug transport and this mechanism can be reversed by calcium channel blockers, while the ADM resistance mechanisms are partly related to drug efflux and only this mechanism of the ADM resistance can be modulated by calcium channel blockers. Calcium channel blockers also potentiate the drug effects, especially that of vinca alkaloids, in innately resistant tumors cells, indicating that such innate resistant cells also share a similar resistance mechanism to that observed in acquired drug resistance. From these results, the mechanisms of acquired and innate drug resistance are discussed.
固有耐药性以及获得性多药耐药性与癌症化疗的无效性和失败直接相关。这种耐药性的机制，尤其是固有耐药性的机制，尚未完全阐明。我们通过持续药物暴露建立了人髓性白血病K562的长春新碱（VCR）和阿霉素（ADM）耐药亚系。这些耐药亚系含有双微体染色体，并表达一种分子量为180,000道尔顿的糖蛋白。对这些耐药亚系中几个分离克隆的VCR和ADM敏感性分析显示，这两种耐药机制之间存在紧密关系。然而，ADM耐药亚系总是对VCR高度耐药，但VCR耐药亚系不一定对ADM高度耐药，这表明ADM和VCR耐药存在不同机制。钙通道阻滞剂抑制这些耐药肿瘤细胞中的药物外流，从而克服耐药性。在VCR和ADM耐药细胞高度交叉耐药的抗肿瘤药物中观察到更强的增效作用。钙通道阻滞剂对VCR的增效作用总是高于ADM，对VCR耐药性更强的克隆通常积累的VCR较少，且VCR外流率通常较高。这些结果可能表明，VCR耐药的主要机制可能是药物转运缺陷，这种机制可被钙通道阻滞剂逆转，而ADM耐药机制部分与药物外流有关，且只有这种ADM耐药机制可被钙通道阻滞剂调节。钙通道阻滞剂还能增强固有耐药肿瘤细胞中的药物作用，尤其是长春花生物碱的作用，这表明此类固有耐药细胞也具有与获得性耐药中观察到的类似耐药机制。根据这些结果，对获得性和固有耐药性的机制进行了讨论。
