PHARMACOLOGY

（申请人描述）预备化疗方案在乳腺癌高剂量治疗的结果中起着关键作用。任何一种方案所产生的肿瘤缩小程度无疑与患者肿瘤的药物敏感性有关。肿瘤细胞对高剂量环磷酰胺、顺铂、BCNU （CPB）方案中使用的药物敏感性的许多生化决定因素现在已经被描述，并且可以在肿瘤组织中测量。该项目的第一个具体目标是测量在初始治疗前、诱导治疗后、持续或复发肿瘤的高剂量治疗后采集的乳腺癌样本中肿瘤对烷基化剂反应的已知决定因素。这些信息将与抗肿瘤效果和生存相关，以确定在CPB治疗失败中起主要作用的机制。然后，我们预期使用这些数据来证明耐药调节剂策略的临床实施。我们最可能的初始目标将是使用药物0-6-苄基鸟嘌呤来调节被认为负责BCNU抗性的酶（0-6-烷基转移酶）。任何方案的抗肿瘤效果和毒性也明显与肿瘤和正常组织所暴露的药物的活性成分的浓度有关。有研究表明，基于药代动力学的布苏凡个体剂量调节可以减少静脉闭塞疾病的发生率，并确保充分的治疗药物暴露。我们也知道，其他化疗药物和辅助药物，如止吐药，会干扰CPB中使用的药物的代谢和药代动力学。因此。该项目的第二个具体目标是确定环磷酰胺、BCNU和顺铂在治疗患者中的药代动力学，并将这些信息与对患者的治疗和毒性作用联系起来。在这些相关性的基础上，我们将开发基于药代动力学的剂量调节算法，以避免与肺部和其他主要毒性相关的高剂量药物暴露，并确保适当的药物治疗暴露。

DESCRIPTION: (Applicant's Description) The preparative chemotherapy regimen plays a critical role in the outcome of high dose therapy for breast cancer. The extent of the tumor reduction produced by any regimen is undoubtedly related to the drug sensitivity of the patient's tumor. Many biochemical determinants of the sensitivity of tumor cells to the agents used in the high-dose cyclophosphamide, cisplatin, BCNU (CPB) regimen have now been described, and can be measured in tumor tissue. The first specific aim of this project is to measure known determinants of tumor response to alkylating agents in breast cancer samples taken prior to initial therapy, after induction therapy, and after high dose therapy in persistent or recurrent tumor. This information will be correlated with antitumor effect and survival, in order to identify those mechanisms which play a major role in the failure of CPB therapy. We then anticipate using these data to justify clinical implementation of drug resistance modifier strategies. Our most likely initial target will be modulation of the enzyme which is thought responsible for BCNU resistance (0-6-alkyltransferase) using the drug 0-6- benzylguanine. The antitumor effect and the toxicity of any regimen are also obviously related to the concentrations of the active components of the drugs to which tumor and normal tissues are exposed. It has been shown that pharmacokinetic based individual dose modulation of busulfan can reduce the incidence of veno- occlusive disease and ensure adequate therapeutic drug exposure. We also know that other chemotherapy agents and auxiliary drugs such as antiemetics will interfere with the metabolism and pharmacokinetics of the agents used in CPB. Therefore. the second specific aim of this project is to define the pharmacokinetics of cyclophosphamide, BCNU, and cisplatin in the patients treated, and to correlate this information with the therapeutic and toxic effects on the patients. On the basis of these correlations, we will develop pharmacokinetic-based dose modulation algorithms to avoid high drug exposures which are associated with pulmonary and other major toxicities, and to ensure the delivery of appropriate therapeutic exposures of the agents.