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: 7274238
• 负责人: BARRY GOLD
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274238
• 关键词: 3-aminobenzamide; 3-deazaadenine; 3-methyladenine; 3-methyladenine-DNA glycosylase; 3-methyladenine-DNA glycosylase I; 7-methylguanine; Abbreviations; Affect; Affinity; Alkanesulfonates; Alkylating Agents; Alkylating Antineoplastic Agents; Alkylation; Animal Model; Antineoplastic Agents; Base Excision Repairs; Binding; Biological; Biological Assay; Biological Availability; Biological Effect of Chemicals; Calorimetry; Carcinogens; Carmustine; Cell Death; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Clinical; Colony-Forming Units Assay; DNA; DNA Adducts; DNA Alkylation; DNA Binding; DNA Damage; DNA Repair; DNA Sequence; DNA lesion; DNA-Directed DNA Polymerase; Dependency; Dipeptides; Distamycin; Distamycins; Embryo; End Point; Environment; Equilibrium; Escherichia coli; Excision; Fibroblasts; Figs - dietary; Frequencies; Genes; Glioblastoma; Glioma; Guanine; HPRT1 gene; Human; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; In Vitro; Incidence; Individual; Induced Mutation; Injection of therapeutic agent; Lesion; MGMT gene; Malignant Neoplasms; Measurement; Measures; Methyl Methanesulfonate; Methylnitrosourea; Minor Groove; Mismatch Repair; Mus; Mutagenesis; Mutation; Mutation Analysis; Netropsin; Nitrosourea Compounds; Nucleotide Excision Repair; Nude Rats; O(6)-Methylguanine-DNA Methyltransferase; O-(6)-methylguanine; Patients; Pattern; Peptides; Play; Poly(ADP-ribose) Polymerases; Polymerase; Process; Propane; Pyrroles; Rattus; Relative (related person); Resistance; Risk; Role; Second Primary Cancers; Shuttle Vectors; Single-Stranded DNA; Site; Specificity; Structure; TP53 gene; Testing; Thioguanine; Time; Titrations; Toxic effect; Transferase; Tumorigenicity; Yeasts; adduct; alkyl group; analog; base; cell killing; cytotoxic; cytotoxicity; design; dimethyl sulfate; ds-DNA; improved; in vivo; methyl lexitropsin; mutant; neoplastic cell; physical property; repaired; research study; temozolomide; tumor; uptake

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剂引起的细胞毒性和诱变中起关键作用。尽管诱变和细胞死亡不一定会机械上重叠，但许多DNA病变都会诱导这两个生物学终点。这一点在临床环境中大大暴露，其中二次癌症的显着发生率归因于对原发性癌症患者的抗肿瘤剂患者的治疗。由于DNA仍然是抗癌剂的极具吸引力的靶标，因此必须识别和消除正面病变的形成，同时保持那些有选择地诱导细胞毒性的病变。我们的假设是，N3-甲基趋化（3-MEA）病变的选择性形成是一种杀死细胞的方法，同时最大程度地减少了与次级癌症相关的突变。为了研究这个问题，我们合成了[1-甲基-4- [1-甲基4-（3-（甲氧化磺酰基） - （丙烷型）吡咯-2-羧酰胺]丙烯-2-羧酰基-2-羧酰基]丙烷（me-lex），丙烷（me-lex），有选择地提供3-MEA的甲基化二肽。在AIM 1中制备的化合物诱导的凹槽DNA病变，并确定DNA修复背景的影响。 3-MEA的模板和3-MEA的稳定类似物。线条测试了对BIS（2-氯乙基）硝基库（BCNU）或替莫唑胺（TMZ）抗细胞毒性作用的人神经胶质瘤的假设，将与ME-LEX及其类似物交叉抗性。将评估ME-LEX的立体定向性肿瘤内递送和类似物对与脑神经胶质瘤无脑膜大鼠存活的影响，并将其与BCNU和TMZ的类似治疗方法进行比较。上述目标的结果应提供有关3-MEA和相关DNA病变的毒性和肿瘤性的有用信息，以及如何避免肿瘤性以改善和更安全的癌症化学疗法。