ANTICANCER DRUG EFFLUX TRANSPORTERS IN DEVELOPMENT

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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.