ANTICANCER DRUG EFFLUX TRANSPORTERS IN DEVELOPMENT

肿瘤细胞对多种化疗药物（MDR）的耐药性是大多数人类癌症治疗的主要障碍。耐多药现象使恶性细胞能够承受许多结构上不相关的抗肿瘤药物的致死剂量。多药耐药的特征是膜相关糖蛋白的过度表达；在这些atp结合盒（ABC）转运体中，研究最多的两个在药物外排中起作用的转运体是p -糖蛋白（P-gly）和多药耐药（相关）蛋白（MRP1）。在个体发育过程中，ABC转运蛋白的表达以及它们的发育如何影响宿主在子宫内和产后早期对治疗药物的反应，目前所知甚少。同样，关于它们在癌症化疗药物对正常组织的毒性中所起的作用以及它们对儿童时期恶性疾病治疗的重要性的资料也很少。因此，我们计划通过检测这些ABC转运蛋白在产前和产后1、3和10-12周龄的组织分布来确定P-gly （mdr1a/1b）和多药耐药蛋白家族（mrps 1-7）的小鼠发育模式，这些组织分布大致对应于胎儿、新生儿、儿童期和成年期。作为模型系统，我们将采用野生型和基因缺陷mrp1 (-/-)；mdr1a / 1 b (- / -);和mrp1 (-/-), mdr1a/1b（-/-）小鼠及其衍生的胚胎成纤维细胞系(a)来评估这些ABC转运蛋白在保护正常组织免受几种抗癌药物影响方面的作用，特别是强调它们与长春新碱和甲氨蝶呤的关系，包括它们对这些药物的代谢和药代动力学处置的影响；(b)确定缺乏一种或多种ABC转运蛋白的影响，并确定是否存在可能的补偿机制；(c)确定P-gly和MRP转运蛋白家族（MRPs 1-6）在预测儿童癌症对抗肿瘤药物的反应中的作用。因此，我们将获得在儿童癌症中ABC转运蛋白测量的效用信息，以选择最有可能诱导反应的治疗药物，并使用敲除小鼠和细胞系作为模型系统来估计ABC转运蛋白对正常组织中抗癌药物的毒性和处置的作用。

Resistance of tumor cells to multiple chemotherapeutic agents (MDR) is a major obstacle to the treatment of most human cancers. The phenomenon of MDR confers upon malignant cells the ability to withstand exposure to lethal doses of many structurally unrelated antineoplastic agents. Multidrug resistance has been characterized by the overexpression of membrane-associated glycoproteins; the two most studied of these ATP-binding cassette (ABC) transporters which have a role in drug efflux are the P-glycoprotein (P-gly) and the multidrug resistance (-associated) protein (MRP1). Little is known about the expression of the ABC transporters during ontogeny and how their development impacts the host response to therapeutic agents in utero and in early postnatal life. Similarly, little information is available on their role in the toxicity of cancer chemotherapeutic agents to normal tissues and their importance to the treatment of malignant diseases during childhood. Accordingly, we plan to determine the murine development patterns of the P-gly (mdr1a/1b) and the multidrug resistance protein family (mrps 1-7) by examining the tissue distribution of these ABC transporters prenatally and postnatally at 1, 3, and 10-12 weeks of age, corresponding approximately to the fetal, newborn, childhood and adulthood developmental periods. As model systems we will employ wild-type and genetically deficient mrp1 (-/-); mdr1a/1b(-/-); and mrp1 (- /-), mdr1a/1b(-/-) mice and embryonic fibroblast cell lines derived therefrom (a) to evaluate the role of these ABC transporters in protecting normal tissue from several anticancer agents, particularly stressing their relationships to vincristine and methotrexate, including their impact on the metabolism and pharmacokinetic disposition of these drugs; (b) to determine the impact of the absence of one or more of the ABC transporters, as well as determine the presence of possible compensatory mechanisms; and (c) to ascertain the involvement of the P-gly and the MRP family of transporters (MRPs 1-6) in the prediction of response of childhood cancers to antineoplastic agents. Thus, we will obtain information on the utility of measurements of the ABC transporters in childhood cancers in selecting therapeutic agents with the greatest potential to induce response and on the use of knockout mice and cell lines as model systems to estimate the role of the ABC transporters on the toxicity to and disposition of anticancer agents in normal tissues.