Basis for effective combination cancer chemotherapy with antimetabolites
Basis for effective combination cancer chemotherapy with antimetabolites
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DOI：
10.1016/s0163-7258(00)00086-3
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发表时间：
2000-08-01
影响因子：
13.5
通讯作者：
Ackland, SP
中科院分区：
文献类型：
--
作者：
Peters, GJ;van der Wilt, CL;Ackland, SP
大多数目前的癌症化疗方案由基于疗效和缺乏重叠毒性的经验设计的组合组成。在联合用药的开发中，有几个方面经常被忽视：（1）药物之间可能的代谢和生物相互作用，（2）时间安排，以及（3）不同的药代动力学特征。抗代谢药广泛用于治疗各种白血病和实体瘤的化疗组合。理想情况下，两种或更多种药物的组合应该比单独使用每种药物更有效（协同作用），尽管相加甚至拮抗组合可能导致临床上更高的治疗功效。中位药效分析法是最广泛使用的体外评价复方制剂的方法之一。经典的有效的抗代谢物-（抗）代谢物组合的几个例子进行了讨论，如甲氨蝶呤与6-巯基嘌呤或甲酰四氢叶酸（儿童）白血病和5-氟尿嘧啶（5 FU）与甲酰四氢叶酸在结肠癌。最近的组合包括用氟达拉滨和阿糖胞苷治疗急性髓性白血病。目前常用于治疗实体恶性肿瘤的其他组合包括抗代谢药与DNA损伤剂，如吉西他滨与顺铂和5 FU与顺铂类似物奥沙利铂。5 FU和拓扑异构酶抑制剂伊立替康的组合基于伊立替康诱导的DNA损伤的修复减少。这些组合可以增加细胞凋亡的诱导。后一种药物组合极大地改变了肺癌和结肠癌等无法治愈的癌症的治疗方法，并证明了合理设计的药物组合为治疗实体恶性肿瘤提供了新的可能性。(C)2000 Elsevier Science Inc. All rights reserved.
Most current chemotherapy regimens for cancer consist of empirically designed combinations, based on efficacy and lack of overlapping toxicity. In the development of combinations, several aspects are often overlooked: (1) possible metabolic and biological interactions between drugs, (2) scheduling, and (3) different pharmacokinetic profiles. Antimetabolites are used widely in chemotherapy combinations for treatment of various leukemias and solid tumors. Ideally, the combination of two or more agents should be more effective than each agent separately (synergism), although additive and even antagonistic combinations may result in a higher therapeutic efficacy in the clinic. The median-drug effect analysis method is one of the most widely used methods for in vitro evaluation of combinations. Several examples of classical effective antimetabolite-(anti)metabolite combinations are discussed, such as that of methotrexate with 6-mercaptopurine or leucovorin in (childhood) leukemia and 5-fluorouracil (5FU) with leucovorin in colon cancer. More recent combinations include treatment of acute-myeloid leukemia with fludarabine and arabinosylcytosine. Other combinations, currently frequently used in the treatment of solid malignancies, include an antimetabolite with a DNA-damaging agent, such as gemcitabine with cisplatin and 5FU with the cisplatin analog oxaliplatin. The combination of 5FU and the topoisomerase inhibitor irinotecan is based on decreased repair of irinotecan-induced DNA damage. These combinations may increase induction of apoptosis. The latter combinations have dramatically changed the treatment of incurable cancers, such as lung and colon cancer, and have demonstrated that rationally designed drug combinations offer new possibilities to treat solid malignancies. (C) 2000 Elsevier Science Inc. All rights reserved.