MODULATION OF DRUG RESISTANCE IN CNS TUMORS

描述：(申请人摘要)中枢神经系统肿瘤 对亚硝脲和相关烷化剂的抗性，因为 O6-烷基鸟嘌呤-DNA烷基转移酶(AGT)上调，修复 DNA中鸟嘌呤6位上的细胞毒性烷基损伤。中枢神经系统肿瘤 可通过O6-苄基鸟嘌呤前处理对烷化药物增敏 (BG)，一种使AGT失活的化合物。不幸的是，化学耗尽了 在动物和组织中的AGT会不分青红皂白地耗尽两者的AGT 正常和肿瘤组织，这增加了正常组织的毒性和限制 可以使用的烷基化药物的剂量。申请人有 在培养和培养中完成AGT及其信号(MRNA)的下调 限制和替代蛋氨酸治疗人中枢神经系统肿瘤的实验研究 同型半胱氨酸，它在正常情况下可以有效地转化为蛋氨酸 组织，而不是蛋氨酸依赖型肿瘤。蛋氨酸在人体内的耗竭 蛋氨酸/胆碱缺乏饮食和 外源性甲硫氨酸酶导致小鼠肿瘤停滞 蛋氨酸依赖型肿瘤对正常组织无毒性，如果 同型半胱氨酸同时全身给药。然而，肿瘤 当停止治疗时，生长就会恢复。在停滞期 和肿瘤生长停滞，它们的AGT活性实质上是 减少，使肿瘤对烷基化药物更敏感 对正常组织的毒性增加。在本申请书中，申请人 旨在通过以下方式提高降低血浆蛋氨酸的效率 饮食和药物手段的结合(目标1)，使 AGT减少对多种异种移植物蛋氨酸耗竭的影响 对蛋氨酸耗竭的可变敏感性(目标2)，记录增强的 烷化类药物治疗蛋氨酸耗竭肿瘤的疗效观察 (目标3)，并验证没有不可接受的正常组织毒性 来自这一养生法(目标4)。申请者的长期目标是 发现和开发治疗人类中枢神经系统疾病的新的有效形式 肿瘤。

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.