Hamilton G, Theyer G, Baumgartner G
Klinische Abteilung für Pathophysiologie, Universitätsklinik für Chirurgie, Wien.
Wien Med Wochenschr. 1993;143(19-20):526-32.
Multidrug-resistance (MDR) is a cellular mechanism, which in certain tumors reduces the chemosensitivity of cells to a characteristic group of structural different cytostatic drugs, as anthracyclines, Vinca alkaloids and others, and correlates with a unfavourable clinical prognosis. In MDR-cells the intracellular concentration of cytostatic drugs is reduced due to the action of the mdr-1-gene-encoded P-glycoprotein (P-gp/gp 170), which functions as drug efflux pump with broad substrate specificity. Many calcium channel blockers of all subclasses (phenylalkylamine, dihydropyridine and benzothiazepine type) and other calcium antagonists inhibit the P-gp-mediated drug efflux and represent modulators of MDR (resistance modifiers, chemosensitizers). Since the sensitized tumor cells express no voltage-gated calcium channels, the induction of changes in intracellular free calcium showed no effect on MDR and the MDR-activity of antagonists is not correlated with their cardiovascular effects, the chemosensitization by these drugs is independent from their action on calcium channels and Ca(++)-regulation. Photoaffinity labelling with reactive derivatives proved the direct competitive interaction of calcium antagonists with the binding site of P-gp for cytostatic drugs as mechanism of action. The MDR-modulation of the doxorubicin or Vinca alkaloid resistance of tumor cells in vitro by verapamil and other calcium channel blockers was confirmed in vivo as increased survival length in mice with tumor transplants in combination with cytostatic therapy. The clinical application of calcium antagonists is limited by their severe cardiovascular side effects associated with the high concentrations required for successful reversal of MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
多药耐药性（MDR）是一种细胞机制，在某些肿瘤中，它会降低细胞对一组结构不同的细胞抑制药物（如蒽环类药物、长春花生物碱等）的化学敏感性，并且与不良的临床预后相关。在多药耐药细胞中，由于mdr-1基因编码的P-糖蛋白（P-gp/gp 170）的作用，细胞抑制药物的细胞内浓度降低，P-糖蛋白作为具有广泛底物特异性的药物外排泵发挥作用。所有亚类的许多钙通道阻滞剂（苯烷基胺类、二氢吡啶类和苯并硫氮杂䓬类）以及其他钙拮抗剂可抑制P-糖蛋白介导的药物外排，是多药耐药性的调节剂（耐药修饰剂、化学增敏剂）。由于致敏的肿瘤细胞不表达电压门控钙通道，细胞内游离钙变化的诱导对多药耐药性没有影响，且拮抗剂的多药耐药活性与其心血管效应无关，因此这些药物的化学增敏作用与其对钙通道和Ca(++)调节的作用无关。用反应性衍生物进行光亲和标记证明，钙拮抗剂与P-糖蛋白上细胞抑制药物的结合位点存在直接竞争相互作用，这是其作用机制。维拉帕米和其他钙通道阻滞剂在体外对肿瘤细胞阿霉素或长春花生物碱耐药性的多药耐药性调节在体内得到证实，即与细胞抑制治疗联合应用时，可延长荷瘤小鼠的存活时间。钙拮抗剂的临床应用受到其严重心血管副作用的限制，这些副作用与成功逆转多药耐药性所需的高浓度有关。（摘要截选至250字）
