P450 PHENOTYPE AND CHEMOTHERAPY TOXICITY IN THE ELDERLY

描述（由申请方提供）：毒性和 对化疗的治疗反应仍然是癌症治疗中的主要问题 治疗 这项工作的长期目标是更好地了解 药理学和药物遗传学决定因素， 可变性，以便个性化化疗，以最大限度地提高效益， 将毒性降到最低。 这在老年癌症患者中尤其重要， 常规排除治疗或经验性排除的组 剂量降低。 这项研究计划的中心假设是， 相关药物代谢酶的个体活性或表型， 这可以在床边用精心挑选的代谢产物来确定。 “探针”可以预测患者的药代动力学（PK）， 化疗 此外，这些基于探针的测试的结果可以是 纳入模型，以更好地定制剂量。 靶向的酶 这一建议是细胞色素P450（CYP），特别是酶 CYP 2和CYP 3家族，它们代表了氧化的主要途径， 药物在肝脏中的代谢。 患者间差异较大， 活跃度。 在许多CYP中存在已知的遗传多态性，但是， 在癌症患者中基因型和表型可能没有很好的相关性。 在 此外，与年龄相关的BMPs表达下降可能是一个关键因素， 这个年龄段的毒性增加。 基于探针的检测， 这些酶中的一些已经形成了表型，但其他酶还没有 本建议探讨了探测试验的价值， 紫杉醇和长春瑞滨的药代动力学和毒性。 紫杉醇是 主要经CYP 2C 8和CYP 3A 4代谢，长春瑞滨经CYP 3A 4代谢。 的 第一个试验是每周紫杉醇给药的剂量递增研究， 新的时间表，针对肺或乳腺癌的老年患者 癌 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）和一种基于探针的新型CYP 2C 8测定法 （罗格列酮）将进行试点测试。 药物代谢表型将 与紫杉醇清除率和毒性相关，预测模型将 在未来的研究中进行设计和前瞻性验证。 cyp 2c 8和cyp 3a 4 还将探索基因型-表型相关性。 在第二次临床 试验，年龄相关的CYP 3A 4活性下降及其对清除率的影响， 将评价用长春瑞滨治疗的患者的中性粒细胞减少症。 我再次重申， 将设计预测模型， 探讨了 所描述的研究项目构成了五年职业生涯的核心 伊丽莎白·迪斯博士的发展计划，助理教授在 血液学/肿瘤学分部。 她的导师保罗·沃特金斯博士是 药物遗传学和药物代谢领域，是 GCRC。 共同导师Beverly Mitchell博士是申请人的部门主管 是Lineberger综合癌症中心的副主任 （LCCC）。 他们提出了一个结合教学和临床研究的经验 利用LCCC的资源，促进Dees博士发展成为一名独立的临床研究者，具有药代动力学和药物表型分析方面的专业知识 代谢酶 他们精心挑选了一批 合作者和顾问，以协助研究项目和博士。 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.