MODULATION OF DRUG RESISTANCE IN CNS TUMORS

中枢神经系统肿瘤耐药性的调节

• 批准号: 6541032
• 负责人: DEMETRIUS Michael KOKKINAKIS
• 金额: $ 7.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541032
• 关键词: alkylating agents; alkyltransferase; antineoplastics; carbon sulfur lyase; carmustine; central nervous system neoplasms; clinical research; cystine; dietary restriction; drug resistance; enzyme activity; glioma; human tissue; laboratory mouse; medulloblastoma; methionine; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; pharmacogenetics; xenotransplantation

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.

描述：（申请人的摘要）中枢神经系统（CNS）肿瘤是 对亚硝基脲和相关烷化剂具有抗性， 上调O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT），修复 DNA中鸟嘌呤6位的细胞毒性烷基损伤。 CNS肿瘤 可通过用O 6-苄基鸟嘌呤预处理对烷化剂增敏 (BG)，一种使AGT失活的化合物。 不幸的是，化学消耗 AGT在动物和组织中产生不加选择的AGT耗竭， 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。 申请人已经 在培养物中完成AGT及其信号（mRNA）的下调， 通过限制甲硫氨酸和替代甲硫氨酸的人CNS肿瘤异种移植物 高胱氨酸，它是有效地转化为蛋氨酸，由正常的 组织，但不是由甲硫氨酸依赖性肿瘤。 中甲硫氨酸的耗尽 蛋氨酸/胆碱缺乏饮食和 甲硫氨酸酶的外源性给药导致肿瘤停滞， 甲硫氨酸依赖性肿瘤对正常组织无毒性，如果 高胱氨酸同时全身给药。 然而，肿瘤 停止治疗时生长恢复。 在停滞期 和生长停滞，它们的AGT活性基本上是 减少，使肿瘤对烷化剂更敏感， 增加对正常组织的毒性。 在本申请中，申请人 寻求通过以下方法提高血浆甲硫氨酸的降低效率： 饮食和药理学方法的组合（目的1），将 在各种异种移植物中， 对甲硫氨酸消耗的敏感性可变（目标2），记录增强的 烷基化药物治疗甲硫氨酸缺失肿瘤的疗效 (Aim 3）、并验证无不可接受的正常组织毒性 从这个方案（目标4）。 申请人的长期目标是 鉴定和开发用于人类CNS新的和有效的治疗形式 肿瘤的

项目成果

Characterization of initiated cells in N-methylnitrosourea-induced carcinogenesis of the CNS in the adult rat.

N-甲基亚硝基脲诱导成年大鼠中枢神经系统癌变过程中启动细胞的表征。

• DOI: 10.1093/neuonc/3.2.99
• 发表时间: 2001
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Kokkinakis,DM;Watson,ML;Honig,LS;Rushing,EJ;Mickey,BE;ScholdJr,SC
• 通讯作者: ScholdJr,SC