Chemotherapy Toxicity: Reduction via Urea Cycle Support

化疗毒性：通过尿素循环支持减少

• 批准号: 6796322
• 负责人: BRIAN W CHRISTMAN
• 金额: $ 28.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796322
• 关键词: arginine; bone marrow transplantation; citrulline; clinical research; combination cancer therapy; cyclophosphamide; drug adverse effect; enzyme inhibitors; genetic polymorphism; genotype; human subject; human therapy evaluation; ligase; metabolism disorder; metabolism disorder chemotherapy; neoplasm /cancer genetics; neoplasm /cancer therapy; nonHodgkin' s lymphoma; nutrition aspect of cancer; nutrition related tag; patient oriented research; pharmacogenetics; single nucleotide polymorphism; urea cycle

The use of hematopoeitic stem cell support in conjunction with escalated dose chemotherapy is increasing as therapy for selected malignancies and autoimmune disorders. Effective therapy is hampered by regimen-related toxicities, such as hepatic venocclusive disease (HVOD) and acute lung injury (ALI). Often HVOD precedes the development of ALI and multiple organ failure after BMT. We have recently developed evidence indicating severe, chemotherapy-induced disturbance in the function of the hepatic urea cycle. Baseline urea cycle function has important prognostic significance--patients with inferior urea cycle function have a 10-fold increase in the risk of developing HVOD. We have also discovered a novel, population-based, exonic, single nucleotide polymorphism (SNP) in carbamyl phosphate synthetase-1 (CPS-1), the rate limiting enzyme in urea cycle function. Patients with this SNP have a markedly reduced incidence of HVOD, resolution of ALI if it occurs, and improved short term survival after BMT. We therefore propose a series of studies aimed at expanding our knowledge about the effects of chemotherapy on in vivo urea cycle function. We plan to better define the magnitude and duration of such effects, refine the relative risk estimates for the different CPS-1 SNP genotypes, determine the optimal agent for supporting urea cycle function in vivo, and conduct a Phase II trial of citrulline augmentation in patients undergoing BMT. Parallel in vitro studies will help decipher the mechanisms by which cyclophosphamide alters the function of CPS-1.

随着选定恶性肿瘤和自身免疫性疾病的治疗，造血干细胞载体的使用与升级的剂量化疗一起增加。有效的治疗受到与方案相关的毒性的阻碍，例如肝粘液性疾病（HVOD）和急性肺损伤（ALI）。 HVOD通常是在BMT后ALI和多器官衰竭的发展之前。我们最近开发了证据，表明肝尿素周期功能上严重的化学疗法引起的干扰。 基线尿素周期功能具有重要的预后意义 - 尿素周期次尿周期功能的患者的发展风险增加了10倍。我们还发现了一种新型的，基于人群的，外显子，单核苷酸多态性（SNP）中的磷酸磷酸合成酶-1（CPS-1），这是尿素周期功能中速率限制酶的速率。该SNP患者的HVOD发病率明显降低，如果发生ALI，则分辨出了BMT后的短期生存。因此，我们提出了一系列研究，旨在扩大我们对化学疗法对体内尿素周期功能的影响的了解。 我们计划更好地定义此类效应的幅度和持续时间，完善不同CPS-1 SNP基因型的相对风险估计，确定支持体内尿素周期功能的最佳剂，并对BMT患者进行Citrulline增强的II期试验。平行的体外研究将有助于破译环磷酰胺改变CPS-1功能的机制。