CYTOCHROME P450 PHARMACOGENETICS AS A PREDICTOR OF TOXICITY AND CLINICAL EFFI

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。无论有没有额外的细胞毒性或激素治疗，联合使用蒽环类药物和环磷酰胺是女性浸润性乳腺癌常见的标准治疗方法。不幸的是，并不是所有的女性都能用这种方法长期存活，而且毒性很常见。育龄妇女特别关注的一个问题是，治疗会导致生育能力的永久性丧失。除了过早绝经对生殖的心理社会影响外，其他相关的负面后遗症包括潮热和可能与骨骼相关的不良后果。阿霉素的特殊毒性包括恶心和呕吐、骨髓抑制、血小板减少和心功能不全(与剂量相关)。虽然多种因素都会影响治疗的有效性和毒性，但其中一个重要的变量是宿主代谢和清除化合物的能力。因此，除了选择的药物和给药的总剂量外，改变化疗药物新陈代谢和排泄的细胞色素P450(CYP450)酶的多态性可能会影响疗效和毒性。先前的一项回顾性队列研究确定了用单药环磷酰胺治疗的狼疮性肾炎患者中预测卵巢早衰的选定的CYP450酶基因。这项研究的目的是描述在一组患有早期乳腺癌的绝经前妇女中，基因变异在过早绝经、潮热和其他毒性反应中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The combination of an anthracycline and cyclophosphamide with or without additional cytotoxic or hormonal therapy represents a common standard approach to therapy in women with invasive breast cancer. Unfortunately, not all women enjoy long term survival with this approach and toxicity is common. A particular concern among women of reproductive age is the permanent loss of fertility secondary to therapy. In addition to the psycho-social impact of premature menopause with regard to reproduction, other associated negative sequelae include hot flashes and possible adverse bone-related consequences. The specific toxicities of doxorubicin include nausea and vomiting, myelosuppression, thrombocytopenia, and cardiac dysfunction (dose-related). While multiple factors influence both the efficacy and the toxicity of therapy, one important variable is the ability of the host to metabolize and clear a compound. Thus, in addition to the agent selected and the total dose administered, polymorphisms of the cytochrome P450 (CYP450) enzymes that alter the metabolism and excretion of chemotherapeutic drugs may have an impact on efficacy and toxicity. A prior retrospective, cohort study identified selected CYP450 enzyme genotypes which predicted for premature ovarian failure in lupus nephritis patients treated with single agent cyclophosphamide. The goal of this study is to delineate the role of genetic variations in premature menopause, hot flashes, and other toxicities in a cohort of premenopausal women with early breast cancer.