Pharmacogenetic Determinants of Vinca Alkaloid Response

研究人员的长期职业目标是成为一名独立的临床医生-科学家和教育家 儿科药理学、药物遗传学和儿科血液学/肿瘤学领域。此应用程序 包括临床研究技能的正式教学培训和旨在形成 为从事临床研究奠定了基础。通过参加印第安纳大学K30项目， 申请者将接受临床药理学研究生涯所需的教学培训。这个 候选人得到了儿科主席和GCRC主任的全力支持，并将履行 她的研究是在出色的临床研究环境中进行的。拟议的项目旨在确定哪些 酶参与长春花碱的处置，以及这些酶的遗传多态是否 携带长春花碱的膜转运蛋白预示着性情、疗效和 毒性。尽管长春花碱在肿瘤学中的应用由来已久，但细胞色素P450的确切作用 酶的性质在很大程度上仍然是未知的。这一点很重要，因为没有明确的 解释了这些药物在药代动力学上的显著差异。结果, 可预测长春花碱毒性和结局的药代动力学或药物遗传学参数有 没有被确认身份。这项建议的第一个目标是鉴定长春花碱的主要代谢物。 生物碱、与其产生相关的酶及其米氏动力学定量 这些酶的参数。第二个目的是调查药物遗传多态的影响 在相关药物代谢酶和转运体上对长春花碱的药代动力学、毒性和 对儿童和成人癌症患者的疗效。通过这些项目，这位调查员将向她努力 长期研究目标是了解药物代谢酶的遗传多态是如何， 受体和转运体影响药物在儿童和成人癌症患者中的疗效和毒性。

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.