Induction of MGMT as a Strategy for Chemoprevention

诱导 MGMT 作为化学预防策略

基本信息

批准号：
7483274
负责人：
KALKUNTE S SRIVENUGOPAL
金额：
$ 7.43万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-10 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483274
关键词：
4-oxothiazolidine Accounting Alkylating Agents Alkylation Amino Acids Animals Antineoplastic Agents Antioxidants Attention Attenuated Automobile Driving Biological Assay Bone Marrow Bone Marrow Stem Cell Brain Cancer cell line Carboxylic Acids Carcinogens Carmustine Catabolism Cells Chemoprevention Chemoprotection Clinical Trials Colon Colon Carcinoma Curcumin Cysteine DNA DNA Damage DNA Repair DNA Repair Enzymes DNA biosynthesis DNA lesion DNA repair protein Data Drug resistance Elevation Enzymes Ethanol Exposure to Food Frequencies Genes Genetic Transcription Genome Genus Cola Glioma Glutathione Guanine Hematopoietic System Hematopoietic stem cells Hepatic Hepatic Tissue Human Hypoxanthine Phosphoribosyltransferase Immunohistochemistry Induced Mutation Kidney Lesion Link Literature Liver Lung MGMT gene Malignant Neoplasms Measures Meat Medicinal Plants Messenger RNA Mismatch Repair Mus Mutation Nitroso Compounds Normal tissue morphology O(6)-Methylguanine-DNA Methyltransferase O(6)-benzylguanine Oncogenic Perception Peripheral Blood Lymphocyte Pharmaceutical Preparations Phytochemical Pilot Projects Plants Play Poison Polymerase Prodrugs Proliferating Cell Nuclear Antigen Property Protein Biosynthesis Protein Overexpression Proteins Publishing Pyroglutamate Hydrolase Rate Reaction Regulator Genes Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Silymarin Specificity System T-Lymphocyte TP53 gene Therapeutic Thioguanine Thymine Tobacco Toxic Actions Toxic effect Transgenic Mice Translations Trees alkyl group animal tissue attenuation base beta catenin cancer prevention cooking cytotoxic glutathione S-transferase pi inhibitor/antagonist nimbidin novel pre-clinical repaired response suicidal temozolomide treatment duration tumor

项目摘要

DESCRIPTION (provided by applicant): Modulation of DNA repair enzymes, leading to facilitated elimination of carcinogenic lesions is likely to be a 6 novel and successful strategy for cancer prevention. MGMT (O6-methylguanine-DNA-methyltransferase), 6 which elicits a direct reversal of guanine-O6 alkylations, plays a central role in protecting the cellular genome from the mutagenic and toxic actions of endogenous, food-derived, environmental, and therapeutic alkylating carcinogens. A vast amount of epidemiological and research data on the reduction of spontaneous and induced tumors in MGMT transgenic mice, attenuation of Ras and p53 mutations in MGMT-proficient cells and the ongoing strategy of MGMT gene transduction into the bone marrow stem cells for achieving alkylator resistance suggest that MGMT is an excellent and rational target for chemoprevention and perhaps chemoprotection. The long-term objective of this pilot (R03) project is to explore the possibility of augmenting MGMT levels through a dietary approach in human normal tissues including the hematopoietic system using a non-toxic cysteine prodrug and antioxidant plant compounds. We have obtained strong evidence for a marked and reproducible increase of MGMT activity (up to 3-fold) in a variety of human cancer cell lines after exposure to a cysteine prodrug (L-2oxothiazolidine-4-carboxylic acid or OTC), and antioxidant compounds such as silymarin, curcumin and ethanol extracts of several medicinal plants. Increased levels of MGMT mRNA and increased rate of MGMT protein synthesis accounted for the enhanced DNA repair activity. OTC is a non-toxic compound, metabolized by the cellular enzyme, 5-oxoprolinase to generate cysteine, whose availability in turn, increases the intracellular GSH levels greatly. Our hypothesis, built on these observations is that OTC and selected phytochemicals will enhance MGMT expression in animal tissues and attenuate the toxicity of clinically used alkylating agents. The major objective of this 2-year pilot project is to establish the feasibility of chemoprevention and chemoprotection via MGMT in a preclinical setting through the following Specific Aims: 1) Quantitate alterations in MGMT expression in hepatic and non-hepatic tissues including the peripheral blood lymphocytes in mice after OTC and antioxidant (curcumin, silymarin, and nimbidin) administrations. 2) Characterize the effect OTC administration on the levels and extent of BCNU, and temozolomide-induced mutations and toxicity in mice. In Specific Aim 1, The DNA repair activity of MGMT, mRNA and protein levels in liver, lung, colon, brain, peripheral blood lymphocytes, and hepatic mRNA levels will be measured after chemopreventative treatments. The treatment duration required for sustained elevation of the repair protein will be assessed. Specific Aim 2 will investigate the mutation frequencies in the Hprt gene of splenic T-lymphocytes, parameters of hematological and overall toxicities induced by BCNU and temozolomide in animals pretreated with OTC. The study promises to pave way for clinical trials of MGMT-targeted chemopreventative strategies. Further, because GSH and GST-pi, likely to be induced, these approaches will provide multiple benefits.

描述（由申请人提供）： DNA修复酶的调节，导致促进致癌性病变的促进，可能是一种6新颖而成功的预防癌症策略。 MGMT（O6-甲基鸟氨酸-DNA-甲基转移酶），6，引起鸟嘌呤-O6烷基化的直接逆转，在保护细胞基因组免受内源性，食物，食物，环境和治疗型烷基化含量的诱变和毒性作用的侵蚀剂中起着核心作用。有关MGMT转基因小鼠自发和诱导的肿瘤减少的大量流行病学和研究数据，MGMT培养细胞中RAS的衰减和p53突变的衰减以及MGMT基因的持续策略以及对骨Marrow干细胞的转导型烷基抗烷基抗抗烷基抗性和化学的目标是MGMMT的一个很棒的IS MGMT和ROTROTINATION IS MGMMT和ROROTINACTINIS IS MGMMT和ROROTINATION。该试验项目的长期目标（R03）项目是通过在包括造血系统的人类正常组织中的饮食方法中探索MGMT水平的可能性，该方法使用无毒的半胱氨酸前药和抗氧化剂植物化合物。我们已经获得了有力的证据表明，在暴露于半胱氨酸前药（L-2-2Oxotizolidine-4-羧酸或OTC）和抗氧化剂的抗氧化剂，姜黄素，姜黄素，姜黄素和乙醇蛋白和乙醇素和多种物质植物和多种物质剂量的抗氧化化合物中，暴露于半胱氨酸前药后，MGMT活性（长达3倍）在各种人类癌细胞系中的明显且可再现。 MGMT mRNA的水平增加和MGMT蛋白合成的速率增加了DNA修复活性的增强。 OTC是一种无毒的化合物，由细胞酶，5-氧化丙酚酶代谢，以产生半胱氨酸，其可用性又会大大提高细胞内GSH水平。我们基于这些观察结果的假设是，OTC和选定的植物化学物质将增强动物组织中的MGMT表达，并减轻临床使用的烷基化剂的毒性。 The major objective of this 2-year pilot project is to establish the feasibility of chemoprevention and chemoprotection via MGMT in a preclinical setting through the following Specific Aims: 1) Quantitate alterations in MGMT expression in hepatic and non-hepatic tissues including the peripheral blood lymphocytes in mice after OTC and antioxidant (curcumin, silymarin, and nimbidin) administrations. 2）表征OTC给药对BCNU水平和程度的影响，以及替莫唑胺诱导的突变和小鼠的毒性。在特定的目标1中，将在化学预防治疗后测量MGMT，MGMT，mRNA和蛋白质水平的DNA修复水平。将评估维修蛋白持续升高所需的治疗持续时间。具体的目标2将研究脾脏T淋巴细胞的HPRT基因，血液学的参数和由BCNU诱导的总体毒性和用OTC预处理的动物中的Temozolomide诱导的总体毒性。该研究有望为MGMT靶向化学预防策略的临床试验铺平道路。此外，由于可能引起的GSH和GST-PI，这些方法将带来多种好处。