The long-term objective of this project is to maximize the therapeutic benefit of combination therapies containing molecularly targeted antiangiogenic/antitumor compounds and conventional cytotoxic chemotherapy. To accomplish this, therapeutic combinations of the following agents will be tested: ZD6474, a novel antiangiogenic/antitumor tyrosine kinase inhibitor acting on both VEGF receptors 1 (flt-1) and 2 (KDR/flk-1) as well as the EGF receptor at sub micromolar levels; docetaxel, a first line chemotherapeutic agent used in breast cancer treatment; and CPT-11, a current chemotherapeutic for colon cancer patients. Therapeutic efficiency of combinations will be evaluated in mouse primary normal and tumor endothelial cells and human breast and colon tumor cells in vitro, because these cell types represent separate compartments of the tumor for therapeutic targeting based on antiangiogenic or antitumor approaches. Since both ZD6474 and the cytotoxic chemotherapeutic agents can elicit either an antiangiogenic or antitumor response based on the concentration and/or duration of drug exposure, initial studies will focus on the concentration and time-dependence of effects in vitro. Pharmacokinetic studies will then be carried out with docetaxel and CPT-11 for the purpose of development of physiologically-based pharmacokinetic (PBPK) models. PBPK models are the most scientifically valid method for simulation of dose and dose-schedules that will produce in vivo drug concentrations and exposures for maximal therapeutic effect in the vascular endothelial or tumor compartment based on in vitro studies. Dose and dose-schedules will be developed for ZD6474 in combination with CPT-11 or docetaxel that optimize the antiangiogenic or antitumor activity of each component of therapy, and these combinations will be tested against human tumor xenografts in nude mice. The predicted antiangiogenic and antitumor activity of each therapeutic protocol will be evaluated in the tumor xenografts by measuring endothelial and tumor cell proliferation and apoptosis. The pharmacokinetic (PK), pharmacodynamic (PD) and therapeutic information from the proposed studies will be used for designing clinical trials using these drug combinations.
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