MODULATION OF MGMT TO ENHANCE BCNU CHEMOTHERAPY

调节 MGMT 以增强 BCNU 化疗

• 批准号: 6514569
• 负责人: Emiko L Kreklau
• 金额: $ 2.41万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6514569
• 关键词: DNA repair; HeLa cells; NOD mouse; Retroviridae; SCID mouse; antineoplastics; bone marrow; carmustine; chemoprevention; clinical research; combination cancer therapy; combination chemotherapy; drug administration rate /duration; drug interactions; enzyme activity; gene therapy; glioma; hematopoietic stem cells; human subject; methylguanine DNA methyltransferase; mutant; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; transfection

The overall objective of this proposal is to investigate 1) the role of DNA repair in chemotherapy resistance, and 2) the efficacy of bone-marrow-directed chemprotection in modulating anticancer chemotherapy. Specifically, the MGMT inhibitor O6- benzylguanine (BG) will be employed to selectively sensitize xenograft tumors to BCNU while simultaneously using retroviral transduction of MGMT mutants to protect bone marrow cells against BCNU-induced myelotoxicity. The point mutants MGMTP140A and MGMTP140K have been shown to be resistant to BG-induced sensitization to BCNU. The first specific aim is to develop an in vivo BG treatment regimen that inhibits wild-type MGMT in xenograft tumor cells for 24 hr. Xenograft human glioma SF767 tumors will be implanted s.c. into NOD/SCID mice, and various BG treatments will be compared. The second specific aim is to demonstrate the ability of transduced MGMT mutants to protect human cells from BG and BCNU combination therapy in vivo. Xenograft tumors of HeLa-mer (methylation repair deficient) cells stably expressing wild-type MGMT, MGMTP140A or MGMGP140K will be treated with the determined BG regimens in combination with BCNU. Resistance to BG-induced MGMT inhibition and BG + BCNU toxicity will be compared in vivo. The third specific aim is to investigate whether combination BG + BCNU chemotherapy can be made selectively cytotoxic to xenograft SF767 tumors in NOD/SCID mice transplanted with MGMTP140A- or MGMTP140K-transduced human bone marrow. MGMT inhibition, tumor regression, myelotoxicity, and other organ toxicities will be evaluated.

该提案的总体目标是研究 1) DNA 修复在化疗耐药中的作用，以及 2) 骨髓定向化学保护在调节抗癌化疗中的功效。 具体来说，MGMT 抑制剂 O6- 苄基鸟嘌呤 (BG) 将用于选择性地使异种移植肿瘤对 BCNU 敏感，同时使用 MGMT 突变体的逆转录病毒转导来保护骨髓细胞免受 BCNU 诱导的骨髓毒性。 点突变体 MGMTP140A 和 MGMTP140K 已被证明对 BG 诱导的 BCNU 致敏具有抗性。 第一个具体目标是开发一种体内 BG 治疗方案，可抑制异种移植肿瘤细胞中的野生型 MGMT 24 小时。 异种移植人类神经胶质瘤 SF767 肿瘤将被皮下植入。进入 NOD/SCID 小鼠，并比较各种 BG 治疗。 第二个具体目标是证明转导的 MGMT 突变体在体内保护人体细胞免受 BG 和 BCNU 联合治疗的能力。稳定表达野生型 MGMT、MGMTP140A 或 MGMGP140K 的 HeLa-mer（甲基化修复缺陷）细胞的异种移植肿瘤将采用确定的 BG 方案与 BCNU 组合进行治疗。将在体内比较对 BG 诱导的 MGMT 抑制的抵抗力和 BG + BCNU 毒性。 第三个具体目标是研究 BG + BCNU 联合化疗是否可以对移植 MGMTP140A 或 MGMTP140K 转导的人骨髓的 NOD/SCID 小鼠中的异种移植 SF767 肿瘤产生选择性细胞毒性。 将评估 MGMT 抑制、肿瘤消退、骨髓毒性和其他器官毒性。

项目成果

Modulation of 1,3-bis-(2-chloroethyl)-1-nitrosourea resistance in human tumor cells using hammerhead ribozymes designed to degrade O6-methylguanine DNA methyltransferase mRNA.

使用旨在降解 O6-甲基鸟嘌呤 DNA 甲基转移酶 mRNA 的锤头核酶调节人类肿瘤细胞中的 1,3-双-(2-氯乙基)-1-亚硝基脲抗性。

• 发表时间: 2001
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Zhang,Q;Ohannesian,DW;Kreklau,EL;Erickson,LC
• 通讯作者: Erickson,LC