INTERACTIONS BETWEEN CYTOTOXIC AND ANTIANGIOGENIC DRUGS

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DESCRIPTION: Angiogenesis inhibitors are a diverse group of agents that control neovascularization, a critical process related to tumor malignancy. Therefore combination cytotoxic (DNA alkylating agents) and anti-angiogenic drug therapy is an emerging chemotherapeutic strategy for cancer treatment, since two distinct pharmacological targets can be affected. The goals of this application are to characterize the pharmacokinetic and pharmacodynamic basis for interactions between cytotoxic drugs (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide ((TMZ)) an the angiogenesis inhibitor, TNP-470 alone and in combination utilizing a xenograft nude rat model. The research plan includes two specific aims that will test 7 hypotheses. Pharmacokinetic measurements will consist of serial plasma and tumor interstitial fluid drug concentrations, collected by microdialysis and pharmacodynamic assessments based on DNA adduct formation. A series of biological measurements will be obtained to understand the mechanistic basis of any drug interactions. The biological data will consist of immunohistochemical measurements of vascular endothelial growth factor (VEGF) its endothelial cell receptors (flk-1 and flt-1), factor VIII, blood flow, and tumor oxygenation. The key hypothesis that will be tested is that angiogenesis inhibitors will alter tumor capillary permeability and accordingly, uptake and toxicity of cytotoxic drugs by mediation of the VEGF pathway. The xenograft rat model developed for this application will use a low and high VEGF expressing glioma cells injected subcutaneously (SC) and intracerebrally (IC) to determine the role of VEGF in drug transport and cytotoxicity. The long range goal is to determine the pharmacological interactions of these cytotoxic drugs and the angiogenesis inhibitor for future utilization in clinical trials.