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.

造血干细胞支持与递增剂量化疗联合使用越来越多地用于治疗某些恶性肿瘤和自身免疫性疾病。有效的治疗受到治疗相关毒性的阻碍，例如肝静脉闭塞性疾病（HVOD）和急性肺损伤（ALI）。 HVOD 通常先于 ALI 和 BMT 后多器官衰竭的发生。我们最近发现的证据表明化疗引起的肝尿素循环功能出现严重紊乱。 基线尿素循环功能具有重要的预后意义——尿素循环功能较差的患者发生 HVOD 的风险增加 10 倍。我们还在氨甲酰磷酸合成酶-1 (CPS-1)（尿素循环功能中的限速酶）中发现了一种新型的、基于群体的外显子单核苷酸多态性 (SNP)。具有该 SNP 的患者的 HVOD 发生率显着降低，ALI（如果发生）可得到缓解，并且 BMT 后的短期生存率得到改善。因此，我们提出了一系列研究，旨在扩大我们对化疗对体内尿素循环功能影响的了解。 我们计划更好地确定此类影响的程度和持续时间，完善不同 CPS-1 SNP 基因型的相对风险估计，确定支持体内尿素循环功能的最佳药物，并在患者中进行瓜氨酸增强的 II 期试验正在进行 BMT。平行体外研究将有助于破译环磷酰胺改变 CPS-1 功能的机制。