P450 PHENOTYPE AND CHEMOTHERAPY TOXICITY IN THE ELDERLY

描述(由申请人提供)：患者之间在有毒和 化疗的治疗反应仍然是癌症的一个主要问题 治疗。这项工作的长期目标是更好地理解 这位住院患者的药理学和药物遗传学决定因素 变异性，使化疗个体化，最大限度地提高效益 将毒性降至最低。这在老年癌症患者中尤其重要， 例行公事地被排除在治疗之外或根据经验被排除在外的组 剂量减少。这项研究计划的中心假设是 个体相关药物代谢酶的活性或表型， 可以在床边使用精心挑选的代谢来确定 “探头”可以预测患者的药代动力学(PK)。 化疗。此外，这些基于探测器的测试的结果可以是 整合到型号中，以更好地量身定制剂量。靶向的酶 这一建议是细胞色素P450(Cyps)，特别是酶 代表氧化的主要途径的细胞色素P2和细胞色素P3家族 药物在肝脏中的代谢。在病人之间有很大的差异 CYP活性。在许多细胞色素P450中存在已知的遗传多态，但细胞色素P450 在癌症患者中，基因型和表型可能没有很好的相关性。在……里面 此外，与年龄相关的CYP表达下降可能是 这个年龄段的毒性增加。基于探针的检测CYP的方法 这些酶中的一些已经形成了表型，但另一些则没有表型 这项建议检验了CYP活性的探针测试在预测中的价值 紫杉醇和长春瑞滨的药代动力学和毒性。紫杉醇是 主要由细胞色素P450 C8和细胞色素P3A4代谢，长春瑞滨主要由细胞色素P3A4代谢。这个 第一个试验是紫杉醇每周给药的剂量递增研究 新的时间表，针对患有肺癌或乳房的老年患者 癌症。详细的药代动力学参数将与毒性相关。 在试验的第二阶段，将使用 红霉素呼气试验(ERMBT)和一种新的基于探针的CYP2C8检测方法 (罗格列酮)将进行试点测试。药物代谢表型将是 与紫杉醇清除量和毒性相关，预测模型将 将在未来的研究中进行设计和前瞻性验证。细胞色素P450 2C8和细胞色素P3A4 还将探讨基因型与表型的相关性。在第二个临床中 试验，与年龄相关的CYP3A4活性下降及其对清除量和 将评估接受长春瑞滨治疗的患者的中性粒细胞减少症。再说一遍， 将设计预测性模型和基因-表型相关性 探索过了。 所描述的研究项目构成了五年职业生涯的核心 该项目助理教授伊丽莎白·迪斯博士的发展计划 血液科/肿瘤科她的导师保罗·沃特金斯博士是 药物遗传学和药物新陈代谢领域，是 GCRC。共同导师贝弗利·米切尔博士是申请者的部门主任 他是莱恩伯格综合癌症中心的副主任 (LCCC)。他们提出了一种教学和临床研究相结合的经验。 利用LCCC的资源将Dees博士培养成具有药代动力学和药物表型鉴定专业知识的独立临床研究员 代谢酶。他们精心挑选了一批 协助研究项目和迪斯博士的合作者和顾问 职业发展。

DESCRIPTION (provided by applicant): Interpatient variability in toxic and therapeutic response to chemotherapy remains a major problem in cancer treatment. The long-term goal of this work is to better understand the pharmacologic and pharmacogenetic determinants of this interpatient variability so as to individualize chemotherapy to maximize benefit and minimize toxicity. This is particularly important in older cancer patients, a group that has routinely been excluded from treatment or empirically dose-reduced. The central hypothesis of this research plan is that an individual's activity, or phenotype, of relevant drug metabolizing enzymes, which can be determined at the bedside using carefully selected metabolic "probes," can predict that patient's pharmacokinetics (PK) for certain chemotherapy. Further, the results of these probe-based tests can be incorporated into models to better tailor dosing. The enzymes targeted in this proposal are the cytochromes P450 (CYPs), particularly the enzyme families CYP2 and CYP3, which represent the major pathways for oxidative metabolism of drugs in the liver. There is large interpatient variation in CYP activity. There are known genetic polymorphisms in many CYPs, but CYP genotype and phenotype may not correlate well in patients with cancer. In addition, age-related decline in CYP expression may be a key factor in increased toxicity in this age group. Probe-based tests that assay CYP phenotype have been developed for some of these enzymes but not for others This proposal examines the value of probe tests of CYP activity in predicting pharmacokinetics and toxicity of paclitaxel and vinorelbine. Paclitaxel is principally metabolized by CYP2C8 and CYP3A4, and vinorelbine by CYP3A4. The first trial is a dose escalation study of weekly paclitaxel administered on a novel schedule, which is targeted toward older patients with lung or breast cancer. Detailed pharmacokinetic parameters will be correlated with toxicity. In the second phase of the trial, CYP3A4 activity will be measured using the erythromycin breath test (ERMBT), and a novel probe-based assay for CYP2C8 (rosiglitazone) will be pilot tested. Drug metabolism phenotype will be correlated with paclitaxel clearance and toxicity, and a predictive model will be designed and prospectively validated in future studies. CYP2C8 and CYP3A4 genotype-phenotype correlations will also be explored. In the second clinical trial, age-related decline in CYP3A4 activity and its impact on clearance and neutropenia in patients treated with vinorelbine will be evaluated. Again, predictive models will be designed and genotype-phenotype correlations explored. The research projects described form the core of a five-year career development plan for Dr. Elizabeth Dees, an Assistant Professor in the Division of Hematology/Oncology. Her mentor, Dr. Paul Watkins, is a leader in the field of pharmacogenetics and drug metabolism and is the Director of the GCRC. Co-mentor, Dr. Beverly Mitchell, is the applicant's Division Director and is the Associate Director of Lineberger Comprehensive Cancer Center (LCCC). They propose a combined didactic and clinical research experience utilizing the resources of the LCCC to foster Dr. Dees's development into an independent clinician investigator with expertise in pharmacokinetics and phenotyping drug metabolizing enzymes. They have assembled a carefully selected group of collaborators and advisors to assist in the research projects and Dr. Dees's career development.