) 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.
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