Pharmacogenetic Determinants of Vinca Alkaloid Response

长春花生物碱反应的药物遗传学决定因素

• 批准号: 7640749
• 负责人: JAMIE L RENBARGER
• 金额: $ 13.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640749
• 关键词: ABCB1 gene; Adult; Antineoplastic Agents; CYP3A4 gene; CYP3A5 gene; Cancer Patient; Chairperson; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Research Curriculum Award; Cytochrome P450; Dose; Dose-Limiting; Drug Interactions; Drug Kinetics; Drug toxicity; Environment; Enzymes; Family; Foundations; Generations; Genetic Polymorphism; Glycoproteins; Goals; Hepatic; In Vitro; Indiana; Individual; Kinetics; Knowledge; Lymphocyte; Malignant Childhood Neoplasm; Malignant Neoplasms; Membrane Transport Proteins; Metabolism; Motor; Myelosuppression; Neutropenia; Outcome; Pediatric Hematology/Oncology; Pediatrics; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacogenetics; Play; Production; Publishing; Pump; Recording of previous events; Research; Research Personnel; Research Proposals; Role; Scientist; Sensory; System; Testing; Therapeutic; Toxic effect; Training; Treatment Efficacy; Universities; Variant; Vinblastine; Vinca Alkaloids; Vincristine; Vinorelbine; Work; cancer therapy; career; design; enzyme activity; improved; oncology; pediatric pharmacology; programs; receptor; response; skills

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.

研究者的长期职业目标是成为一名独立的临床科学家和教育家 儿科药理学、药物遗传学和儿科血液学/肿瘤学领域。这个应用程序 涉及临床研究技能的正式教学培训和旨在形成的重点研究计划 临床研究职业的基础。通过参与印第安纳大学 K30 计划， 申请人将接受临床药理学研究生涯所需的教学培训。这 候选人得到儿科主席和 GCRC 主任的全力支持，并将执行 她在出色的临床研究环境中进行研究。拟议项目旨在确定哪些 酶参与长春花生物碱的处置以及这些酶是否存在遗传多态性 携带长春花生物碱的膜转运蛋白可预测其处置、功效和 毒性。尽管长春花生物碱在肿瘤学中的应用有着悠久的历史，但细胞色素 P450 的确切作用 酶的分布在很大程度上仍然未知。这很重要，因为没有明确的 解释这些药物的药代动力学的显着变化。因此， 可以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 未被识别。该提案的第一个目标是鉴定长春花的主要代谢物 生物碱、参与其生产的酶以及 Michaelis Menten 动力学的定量 这些酶的参数。第二个目标是研究药物遗传学多态性的影响 相关药物代谢酶和转运蛋白对长春花生物碱药代动力学、毒性和 对儿童和成人癌症患者的疗效。通过这些项目，这位调查员将致力于她 长期研究目标是了解药物代谢酶中的遗传多态性， 受体和转运蛋白影响儿童和成人癌症患者的药物疗效和毒性。

项目成果

Simultaneous quantification of vincristine and its major M1 metabolite from dried blood spot samples of Kenyan pediatric cancer patients by UPLC-MS/MS.

• DOI: 10.1016/j.jpba.2021.114143
• 发表时间: 2021-09-05
• 期刊: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
• 影响因子: 3.4
• 作者: Agu, Lorita;Skiles, Jodi L.;Masters, Andrea R.;Renbarger, Jamie L.;Chow, Diana S-L
• 通讯作者: Chow, Diana S-L

Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.

• DOI: 10.1002/pbc.22845
• 发表时间: 2011-03
• 期刊: PEDIATRIC BLOOD & CANCER
• 影响因子: 3.2
• 作者: Egbelakin, Akinbode;Ferguson, Michael J.;MacGill, Emily A.;Lehmann, Amalia S.;Topletz, Ariel R.;Quinney, Sara K.;Li, Lang;McCammack, Kevin C.;Hall, Stephen D.;Renbarger, Jamie L.
• 通讯作者: Renbarger, Jamie L.