CYTOCHROME P450 PHARMACOGENETICS AS A PREDICTOR OF TOXICITY AND CLINICAL EFFICAC

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 蒽环类药物和环磷酰胺联合治疗，有或没有额外的细胞毒性或激素治疗代表了浸润性乳腺癌女性的常见标准治疗方法。 不幸的是，并不是所有的女性都能长期存活，而且毒性很常见。 育龄妇女特别关注的是治疗后永久丧失生育能力。 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的不良骨骼相关后果。 阿霉素的特异性毒性包括恶心和呕吐、骨髓抑制、血小板减少和心功能障碍（剂量相关）。 虽然多种因素影响治疗的功效和毒性，但一个重要的变量是宿主代谢和清除化合物的能力。 因此，除了所选药物和给药剂量外，改变化疗药物代谢和排泄的细胞色素P450（CYP 450）酶的多态性可能对疗效和毒性产生影响。一项既往回顾性队列研究确定了选定的CYP 450酶基因型，这些基因型可预测接受单药环磷酰胺治疗的狼疮性肾炎患者的卵巢早衰。 本研究的目的是描述遗传变异在一组绝经前早期乳腺癌妇女中过早绝经、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, mylosuppression, 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.