Hooijberg J H, de Vries N A, Kaspers G J L, Pieters R, Jansen G, Peters G J
Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2006 Jul;58(1):1-12. doi: 10.1007/s00280-005-0141-1. Epub 2005 Dec 15.
Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.
在过去几十年中，众多报告阐述了多药耐药（MDR）转运蛋白在各种化疗药物疗效中的关键作用。特定的细胞膜相关转运蛋白通过排出多种毒性物质来介导耐药性。尽管已有几篇优秀综述探讨了耐药性的一般方面，但本综述旨在强调其对基于叶酸的化疗药物及其他类型化疗药物疗效的影响。叶酸是许多生物合成过程每日所需的维生素。饮食中补充叶酸可能对包括癌症在内的多种疾病具有保护作用，但叶酸补充也是当前几种癌症化疗方案的重要组成部分。例如，传统上叶酸亚叶酸用于降低白血病中抗叶酸药物的毒性，或增强某些实体瘤中氟嘧啶5-氟尿嘧啶的疗效。最近，也有人指出叶酸能够增强几种结构不相关化疗方案的抗肿瘤活性，如培美曲塞/力比泰和顺铂。此外，我们实验室的研究表明，叶酸可以调节至少两种MDR转运蛋白的表达和活性：多药耐药相关蛋白1（MRP1/ABCC1）和乳腺癌耐药蛋白（BCRP/ABCG2）。因此，补充叶酸可能对化疗产生不同影响：（1）降低毒性，（2）增强抗肿瘤活性，以及（3）诱导与MRP1和BCRP相关的细胞耐药性。在本综述中，将从最佳利用叶酸补充以提高基于抗叶酸化疗及其他类化疗药物的化疗疗效的角度，对这三个方面中MDR蛋白的作用进行更详细的讨论。
