The hypotheses of this proposal are: 1) our models for human medulloblastoma consisting of the continuous human medulloblastoma cell lines and transplantable xenografts TE-671, D283MED and additional lines presently under development, will allow the unique opportunity to analyze specific mechanisms of drug sensitivity, delivery, and resistance in this tumor, and 2) L-phenylalanine mustard (melphalan) and other phenylalanine mustard isomers represent bifunctional alkylating agents highly cytoxic to human medulloblastoma which may be rationally modulated to increase drug delivery and overcome tumor resistance. Accordingly, the specific aims of this proposal are: 1) define the mechanisms that influence melphalan cytotoxicity in human medulloblastoma cell lines in a clonogenic assay, subcutaneous and intracranial human medulloblastoma xenografts in athymic mice and patient medulloblastoma specimens. Specific mechanisms to be examined include: melphalan transport kinetics, total glutathione and glutathione-S-transferase levels, and melphalan-induced DNA damage and repair; 2) to define the effects of agents that alter glutathione metabolism on melphalan by examining (a) cytotoxicity in human medulloblastoma cell lines in a clonogenic assay, (b) cytotoxicity in subcutaneous and intracranial human medulloblastoma xenografts and (c) toxicity in human bone marrow cells(CFU-C) and athymic mice; 3) to determine the potential therapeutic advantage of intra-arterial vs intravenous delivery of melphalan and the cyclophosphamide derivatives. 4-hydroperoxycyclophosphamide and phenylketocyclophosphamide in intracranial human medulloblastoma xenografts in athymic rats. These studies will have direct application to the design of future clinical trials for human medulloblastoma.
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