Selassie C D, Hansch C, Khwaja T A
Department of Chemistry, Pomona College, Claremont, California 91711.
J Med Chem. 1990 Jul;33(7):1914-9. doi: 10.1021/jm00169a014.
Clinical resistance to many antineoplastic agents is a major cause of treatment failure. The well-documented phenomenon addressed as multidrug resistance (MDR) allows cells to withstand exposure to lethal doses of drugs with dissimilar chemical structures, modes of action, and physicochemical properties. In one of the earliest studies on MDR, Biedler and Riehm in an attempt to explain the cross-resistance profile of actinomycin D resistant Chinese hamster cells suggested that molecular weight was an important determinant. Our statistical analysis of their data validates their claim and indeed strongly demonstrates that cross resistance is enhanced by the increased size and hydrophobicity of the antitumor agent. Our preliminary studies with methotrexate-resistant L1210 cells indicates that cross resistance is increased in the case of moderate-sized, hydrophilic drugs. These two studies and others suggest that current chemotherapy regimens may be improved by treating resistant cells with antineoplastic agents displaying physicochemical characteristics opposite to that of the original inducing agent.
对许多抗肿瘤药物的临床耐药性是治疗失败的主要原因。被称为多药耐药（MDR）的这一有充分文献记载的现象使细胞能够耐受暴露于具有不同化学结构、作用方式和物理化学性质的致死剂量药物。在最早关于MDR的研究之一中，比德勒和里姆试图解释对放线菌素D耐药的中国仓鼠细胞的交叉耐药谱，他们认为分子量是一个重要的决定因素。我们对他们数据的统计分析证实了他们的说法，并且确实有力地证明了抗肿瘤药物的尺寸和疏水性增加会增强交叉耐药性。我们对耐甲氨蝶呤的L1210细胞的初步研究表明，对于中等大小的亲水性药物，交叉耐药性会增加。这两项研究以及其他研究表明，通过用具有与原始诱导剂相反物理化学特性的抗肿瘤药物治疗耐药细胞，当前的化疗方案可能会得到改善。
