Chemotherapy Toxicity: Reduction via Urea Cycle Support

在特定的恶性肿瘤和自身免疫性疾病的治疗中，造血干细胞支持与逐步增加的剂量化疗相结合的使用正在增加。有效的治疗受到与方案相关的毒副作用的阻碍，如肝静脉闭塞病(HVOD)和急性肺损伤(ALI)。在骨髓移植后，常先于ALI和多器官功能衰竭的发生。我们最近发现的证据表明，严重的化疗引起的肝脏尿素循环功能紊乱。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。我们还在尿素循环中的限速酶氨基甲酰磷酸合成酶-1(CPS-1)中发现了一种新的基于群体的外显子单核苷酸多态性(SNP)。患有这种SNP的患者明显减少了HVOD的发生率，如果ALI发生了，ALI的消退，并提高了BMT后的短期存活率。因此，我们提出了一系列旨在扩大我们对化疗对体内尿素循环功能影响的知识的研究。我们计划更好地定义这些影响的大小和持续时间，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制剂，并在接受骨髓移植的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.