PHARMACOLOGY

描述：(申请人的描述)准备化疗方案对乳腺癌大剂量治疗的结果起着至关重要的作用。任何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。现在已经描述了肿瘤细胞对大剂量环磷酰胺、顺铂、BCNU(CPB)方案中使用的药物的敏感性的许多生化决定因素，并且可以在肿瘤组织中进行测量。该项目的第一个具体目标是测量乳腺癌样本中已知的对烷化剂的反应决定因素，这些样本在最初治疗前、诱导治疗后以及持续或复发肿瘤的高剂量治疗后采集。这些信息将与抗肿瘤效果和生存期相关，以确定那些在CPB治疗失败中起主要作用的机制。然后，我们预计将使用这些数据来证明耐药调节剂策略的临床实施是合理的。我们最有可能的初始目标是使用药物0-6-苄基鸟嘌呤来调节被认为导致BCNU耐药的酶(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接触的药物活性成分的浓度有关。已有研究表明，基于药代动力学的白消安个体化剂量调节可以减少静脉闭塞疾病的发生率，并保证足够的治疗性药物暴露。我们还知道，其他化疗药物和辅助药物，如止吐剂，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和顺铂在接受治疗的患者中的药代动力学，并将这些信息与患者的治疗和毒性作用相关联。根据这些相关性，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药物暴露，并确保提供适当的治疗性暴露。

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.