DNA Damage: Roles in Toxicity and Mutagenicity

DNA 损伤：在毒性和致突变性中的作用

• 批准号: 6822018
• 负责人: BARRY GOLD
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6822018
• 关键词: DNA damage; DNA methylation; DNA repair; adduct; adenine; alkylating agents; alkylation; antineoplastics; cell line; chemical binding; chemical synthesis; cytotoxicity; drug adverse effect; drug design /synthesis /production; drug related neoplasm /cancer; female; glioma; intermolecular interaction; laboratory rat; mutagens; neoplasm /cancer chemotherapy; nucleic acid structure; pharmacokinetics; tissue /cell culture

DESCRIPTION (provided by applicant): DNA damage plays a critical role in the cytotoxicity and mutagenicity elicited by carcinogens and many clinically used antineoplastic agents. While mutagenesis and cell death do not necessarily overlap mechanistically, many DNA lesions can induce both biological endpoints. This point is dramatically exposed in the clinical setting where a significant incidence of secondary cancers is attributed to the treatment of patients with antineoplastic agents for their primary cancer. Since DNA remains an extremely attractive target for anticancer agents, it is imperative to identify and eliminate the formation of promutagenic lesions while maintaining those that selectively induce cytotoxicity. Our hypothesis is that the selective formation of N3- methyladenine (3-MeA) lesions presents an approach to kill cells while minimizing mutations associated with secondary cancers. To study this issue, we have synthesized [1-methyl-4-[1-methyl 4-(3-(methoxysulfonyl)- (propanamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propane (Me-lex), a methylating dipeptide that selectively affords 3-MeA. The Specific Aims are: (1) To design new minor groove alkylating agents (analogues of Me-lex) with improved activity and bioavailabililty. (2) To understand the cytotoxicity and mutagenicity of specific minor groove DNA lesions induced by the compounds prepared in Aim 1, and to determine the impact of the DNA repair background. (3) To determine the mechanisms responsible for 3- MeA induced stalling of replicative DNA polymerases and translesion synthesis via by-pass polymerases using templates with 3-MeA and a stable analogue of 3-MeA. The effect of DNA sequence on these processes will also be investigated. (4) The cytotoxicity of Me-lex and the analogues synthesized in Aim 1 will be assayed in human glioma cell lines to test the hypothesis that human gliomas resistant to the cytotoxic effects of bis(2-chloroethyl)nitrosourea (BCNU) or temozolomide (TMZ) will not be cross-resistant to Me-lex and its analogs. The effects of stereotactic intratumoral delivery of Me-lex and the analogs on survival of athymic rats with intracerebral human gliomas will be evaluated and compared to similar treatments with BCNU and TMZ. The results of the above aims should provide useful information on the toxicity and tumorigenicity of 3-MeA and related DNA lesions, as well as how tumorigenicity can be avoided to afford improved and safer cancer chemotherapies.

描述（由申请人提供）：DNA 损伤在致癌物和许多临床使用的抗肿瘤药物引起的细胞毒性和致突变性中起着关键作用。虽然诱变和细胞死亡在机制上不一定重叠，但许多 DNA 损伤可以诱导这两种生物学终点。这一点在临床环境中显着暴露，其中继发性癌症的显着发病率归因于使用抗肿瘤药物治疗原发性癌症的患者。由于 DNA 仍然是抗癌药物极具吸引力的靶标，因此必须识别并消除促诱变病变的形成，同时维持那些选择性诱导细胞毒性的病变。我们的假设是，N3-甲基腺嘌呤 (3-MeA) 病变的选择性形成提供了一种杀死细胞的方法，同时最大限度地减少与继发性癌症相关的突变。为了研究这个问题，我们合成了[1-甲基-4-[1-甲基4-(3-(甲氧基磺酰基)-(丙酰胺基)吡咯-2-甲酰胺基]吡咯-2-甲酰胺基]丙烷(Me-lex)，一种选择性提供3-MeA的甲基化二肽。具体目标是：(1)设计新型小沟烷基化剂 （Me-lex 的类似物）具有改善的活性和生物利用度。 (2)了解目的1制备的化合物对特定小沟DNA损伤的细胞毒性和致突变性，并确定DNA修复背景的影响。 (3) 确定 3-MeA 诱导复制 DNA 聚合酶停滞和通过旁路跨损伤合成的机制 使用具有 3-MeA 和 3-MeA 稳定类似物的模板的聚合酶。 DNA 序列对这些过程的影响也将得到研究。 (4) 将在人神经胶质瘤细胞系中测定Me-lex和Aim 1中合成的类似物的细胞毒性，以检验人神经胶质瘤对双(2-氯乙基)亚硝基脲的细胞毒性作用具有抵抗力的假设 (BCNU) 或替莫唑胺 (TMZ) 不会与 Me-lex 及其类似物产生交叉耐药性。将评估立体定向瘤内递送 Me-lex 及其类似物对患有脑内人类神经胶质瘤的无胸腺大鼠的存活的影响，并与 BCNU 和 TMZ 的类似治疗进行比较。上述目标的结果应提供有关毒性和毒性的有用信息。 3-MeA 和相关 DNA 损伤的致瘤性，以及如何避免致瘤性以提供改进和更安全的癌症化疗。