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Selenium protection of bone marrow during chemotherapy

硒对化疗期间骨髓的保护作用

基本信息

批准号：
7477652
负责人：
MARTIN L SMITH
金额：
$ 22.65万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2007-08-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477652
关键词：
Apoptosis Autopsy Biological Assay Blood Cells Bone Marrow CDKN1A gene Cancer Patient Carboplatin Cell Cycle Cell Cycle Checkpoint Cell Cycle Checkpoint Genes Cell Survival Cells Chemotherapy-Oncologic Procedure Clinical Research Clinical Trials Cultured Cells Cysteine DNA Damage DNA Repair Data Dose Dose-Limiting Drug toxicity Electronics Environment Exhibits Flow Cytometry Fostering Funding Generations Genes Genotype Human Indiana University Cancer Center Innovative Therapy Institutes L-Selenomethionine Licensing Malignant Neoplasms Maximum Tolerated Dose Methionine Molecular Molecular Target Mus Mutagenesis Mutation Myelosuppression Normal Cell Null Lymphocytes Oncogenes Organ failure Pancytopenia Pathologist Patients Pediatric Research Pharmaceutical Preparations Platinum Compounds Play Proliferating Range Rate Reporter Genes Research Research Personnel Resource Sharing Role Roswell Park Cancer Institute Selenium Serum Solid Neoplasm TP53 gene Testing Tissues Today Toxic effect Veterinarians Work base cancer cell chemotherapy day gastrointestinal epithelium indexing irinotecan mutant novel oncology oncoprotein p21 programs research study response success taxane tissue/cell culture tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Non-genotoxic selenium in the form of seleno-L-methionine is in clinical trials as an adjunct to conventional chemotherapy. In mice, dramatic cures of xenograft tumors were obtained using selenium in combination with chemotherapy drugs, cures associated with protection from dose-limiting toxicity of bone marrow and other tissues. Dose-limiting toxicity is a major impediment to cure rates of human patients. Selenium protected bone marrow while maintaining antitumor efficacy. Indeed, selenium allowed a doubling or even tripling of the maximum tolerated dose (MTD). It is clear that molecular determinants distinguish cancer cells from normal cells. One important molecular determinant, p53, is modified on key cysteine sulfhydryl residues in selenium-treated cells. Separate from its role in apoptosis, p53 is known to protect cells from DNA damage. Selenium was found to activate the protective functions of p53 and not apoptosis. The hypothesis is that p53 is a molecular target of selenium involved in bone marrow protection. The hypothesis will be tested by three specific aims: Aim 1 will test the hypothesis that selenium protects p53-wildtype bone marrow from chemotherapy-induced myelosuppression by a DNA repair/cell cycle checkpoint mechanism, a mechanism lacking in mice lacking p53, and/or its downstream effector genes involved in DNA repair and cell cycle checkpoints. Aim 2 will test the hypothesis that the mechanism whereby selenium protects wildtype mouse bone marrow is by a bona fide DNA repair/cell cycle checkpoint mechanism, and not an error-prone mechanism. Selenium is predicted to decrease mutagenesis. Aim 3 will test the hypothesis that additional tissues may play a role in chemotherapeutic toxicity, i.e. if selenium protects the bone marrow, damage to other tissues may become dose-limiting. These studies will provide a molecular mechanism for bone marrow protection by selenium in combination with cancer chemotherapeutics, and will foster further clinical studies.

描述（由申请人提供）：硒代-L-甲硫氨酸形式的非基因毒性硒作为常规化疗的辅助手段正在进行临床试验。在小鼠中，使用硒与化疗药物相结合，获得了异种移植肿瘤的显着治愈，这种治愈与保护骨髓和其他组织免受剂量限制性毒性有关。剂量限制性毒性是人类患者治愈率的主要障碍。硒保护骨髓，同时保持抗肿瘤功效。事实上，硒可以使最大耐受剂量（MTD）增加一倍甚至三倍。很明显，分子决定因素将癌细胞与正常细胞区分开来。在硒处理的细胞中，一种重要的分子决定簇 p53 在关键的半胱氨酸巯基残基上发生了修饰。除了在细胞凋亡中的作用之外，p53 还可以保护细胞免受 DNA 损伤。研究发现硒可以激活 p53 的保护功能，但不会激活细胞凋亡。假设 p53 是参与骨髓保护的硒分子靶点。该假设将通过三个具体目标进行检验：目标 1 将检验硒通过 DNA 修复/细胞周期检查点机制保护 p53 野生型骨髓免受化疗诱导的骨髓抑制的假设，这是缺乏 p53 和/或其参与 DNA 修复和细胞周期检查点的下游效应基因的小鼠所缺乏的机制。目标 2 将检验以下假设：硒保护野生型小鼠骨髓的机制是通过真正的 DNA 修复/细胞周期检查点机制，而不是容易出错的机制。硒预计会减少诱变。目标 3 将检验以下假设：其他组织可能在化疗毒性中发挥作用，即如果硒保护骨髓，则对其他组织的损害可能会受到剂量限制。这些研究将提供硒与癌症化疗药物相结合保护骨髓的分子机制，并将促进进一步的临床研究。