Malignant brain tumors of glial origin have proven relatively refractory to current chemotherapy, primarily because of undesirable toxicity to normal tissues. A major objective of oncologic therapeutics is to enhance neoplastic cytotoxicity and minimize undesirable effects to normal cells. One avenue to achieve such a goal employs the novel technology of in vivo gene transfer to endow tumor cells with the capability of converting prodrugs into their active anticancer metabolites. The most widely effective chemotherapeutic agents for brain tumors are the alkylating nitrosoureas. The mustard-like compounds are another class of DNA- alkylating agents. Prodrugs for each of these agents exist: 1) cyclophosphamide (CPA) is an inactive lipophilic compound which can be activated by a cytochrome P450 enzyme (cytochrome P450 2B1) into phosphoramide mustard (PM), a potent DNA-alkylator; 2) Methylpropylchloronitrosourea (MPCNU) is a prodrug which can also be activated by cytochrome P450 enzymes (2E1 and possibly, 2B1) into the active anticancer metabolite, PrCNU. Viral vectors, based on retroviruses and on herpes simplex virus (HSV), will thus be engineered to transfer that rat cytochrome P450 2B1 (or 2E1) gene(s) into rat brain tumor cells. In vitro studies will determine the acquisition of CPA-and MPCNU- susceptibility after infection with either vector (specific aims 1 and 2). An animal model of brain tumors will then be employed to determine whether the above gene therapy strategy shows therapeutic effectiveness. This will entail volumetric analyses of tumor regression, studies on animal survival, histopathologic correlates of regression, studies on toxic effects to normal tissues, assays of CPA and MPCNU metabolites in the blood of treated animals as well as in brain and tumor tissue (specific aims 3 and 4). These studies should provide the necessary information to justify a phase I/II trial of therapy in humans afflicted with malignant glial tumors using genes that will activate alkylating prodrugs.
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