Pharmacogenetic Determinants of Vinca Alkaloid Response

描述（由申请人提供）： 研究者的长期职业目标是成为儿科药理学、药物遗传学和儿科血液学/肿瘤学领域的独立临床科学家和教育家。该申请涉及临床研究技能的正式教学培训和旨在形成临床研究职业生涯基础的重点研究提案。通过参加印第安纳州大学K30项目，申请人将获得临床药理学研究生涯所需的教学培训。候选人得到了儿科主席和GCRC主任的全力支持，并将在出色的临床研究环境中开展研究。拟议的项目旨在确定哪些酶参与了长春花生物碱的处置，以及这些酶和携带长春花生物碱的膜转运蛋白的遗传多态性是否可以预测处置、功效和毒性。尽管长春花生物碱在肿瘤学中的应用历史悠久，但细胞色素P450酶在其分布中的确切作用仍然很大程度上没有得到表征。这一点很重要，因为对于这些药物的药代动力学的显著变异性没有明确的解释。因此，可能预测长春花生物碱毒性和结果的药代动力学或药物遗传学参数尚未确定。本建议的第一个目的是鉴定长春花生物碱的主要代谢产物，参与其生产的酶，以及这些酶的米氏动力学参数的定量。第二个目的是研究相关药物代谢酶和转运蛋白的药物遗传多态性对儿童和成人癌症患者中长春花生物碱药代动力学、毒性和疗效的影响。通过这些项目，这位研究者将致力于她的长期研究目标，即了解药物代谢酶、受体和转运蛋白的遗传多态性如何影响药物在儿科和成人癌症患者中的疗效和毒性。

DESCRIPTION (provided by applicant): The investigator's long-term career objective is to become an independent clinician-scientist and educator in the fields of pediatric pharmacology, pharmacogenetics and pediatric hematology/oncology. This application involves formal didactic training in clinical research skills and a focused research proposal designed to form the foundation for a career in clinical research. Through participation in the Indiana University K30 program, the applicant will receive the didactic training necessary for a research career in clinical pharmacology. The candidate has the full support of the Chairman of Pediatrics and the Director of the GCRC and will perform her research in an outstanding clinical research environment. The proposed projects aim to determine which enzymes are involved in vinca alkaloid disposition and whether genetic polymorphisms in these enzymes and the membrane transporters that carry the vinca alkaloids are predictive of disposition, efficacy and toxicity. Despite the long history of vinca alkaloid use in oncology, the precise roles of the cytochrome P450 enzymes in their disposition remain largely uncharacterized. This is important because there is no definitive explanation for the significant variability in the pharmacokinetics of these drugs. As a result, pharmacokinetic or pharmacogenetic parameters that might predict vinca alkaloid toxicity and outcome have not been identified. The first aim of this proposal involves identification of the major metabolites of the vinca alkaloids, the enzymes involved in their production, and quantification of Michaelis Menten kinetic parameters for these enzymes. The second aim investigates the impact of pharmacogenetic polymorphisms in pertinent drug metabolizing enzymes and transporters on vinca alkaloid pharmacokinetics, toxicity, and efficacy in pediatric and adult cancer patients. Through these projects, this investigator will work toward her long-range research goal of understanding how genetic polymorphisms in drug metabolizing enzymes, receptors, and transporters influence the efficacy and toxicity of drugs in pediatric and adult cancer patients.