MODULATION OF DRUG RESISTANCE IN CNS TUMORS

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DESCRIPTION: (Applicant's Abstract) Central nervous system (CNS) tumors are resistant to nitrosoureas and related alkylating agents because of upregulation of O6-alkylguanine-DNA alkyltransferase (AGT), which repairs the cytotoxic alkyl lesions at the 6-position of guanine in DNA. CNS tumors can be sensitized to alkylating drugs by pre-treatment with O6-benzylguanine (BG), a compound that inactivates AGT. Unfortunately, chemical depletion of AGT in animals and tissues produces indiscriminate depletion of AGT in both normal and tumor tissue, which increases normal tissue toxicity and limits the dose of the alkylating drug that can be used. The applicant has accomplished downregulation of AGT and its signal (mRNA) in cultures and xenografts of human CNS neoplasms by restricting methionine and replacing it with homocystine, which is effectively converted to methionine by normal tissue but not by methionine-dependent tumors. Depletion of methionine in animals with a combination of a methionine/choline deficient diet and exogenous administrations of methioninase results in tumor stasis in methionine-dependent tumors without toxicity to normal tissue, if homocystine is administered systemically at the same time. However, tumor growth resumes when treatment is discontinued. During the period of stasis and growth arrest in the tumors, their AGT activity is substantially reduced, making the tumors more sensitive to alkylating drugs without increasing toxicity to normal tissue. In this application, the applicant seeks to improve the efficiency of reduction in plasma methionine by a combination of dietary and pharmacologic means (Aim 1), correlate the depletion of methionine with AGT reduction in a variety of xenografts with variable sensitivity to methionine depletion (Aim 2), document the enhanced efficacy of treatment with alkylating drugs in methionine depleted tumors (Aim 3), and verify that there is no unacceptable normal tissue toxicity from this regimen (Aim 4). The applicant's long-term objective is to identify and develop new and effective forms of therapy for human CNS tumors.