Chemotherapy Toxicity: Reduction via Urea Cycle Support

造血干细胞支持与递增剂量化疗相结合的使用越来越多地用于特定恶性肿瘤和自身免疫性疾病的治疗。有效的治疗受到方案相关毒性的阻碍，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后多器官衰竭的发展。我们最近有证据表明，化疗引起的肝尿素循环功能的严重紊乱。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。我们还发现了一种新的、基于群体的、外显子的、单核苷酸多态性（SNP）在氨甲酰磷酸合成酶-1 （CPS-1）中，尿素循环功能的限速酶。具有这种SNP的患者HVOD的发生率显著降低，ALI（如果发生）得到缓解，BMT后的短期生存率提高。因此，我们提出了一系列的研究，旨在扩大我们对化疗对体内尿素循环功能的影响的认识。我们计划更好地定义这种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，确定体内支持尿素循环功能的最佳药物，并在BMT患者中进行瓜氨酸增强的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。

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.