肥胖对造血干细胞移植受者环磷酰胺诱导的 DNA 损伤的影响。

Obesity effects on cyclophosphamide-induced DNA damage in hematopoietic cell transplant recipients.

机构信息

University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, 308 Harvard Street SE, 7-115C WDH, Minneapolis, MN 55443, USA.

出版信息

In Vivo. 2012 Sep-Oct;26(5):853-7.

PMID:22949601

Abstract

BACKGROUND

Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA-DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NOR-G crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks.

PATIENTS AND METHODS

Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured.

RESULTS

Overweight/obese patients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obese patients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC(0-∞)) =529.24 vs. 867.99 μcg/mlh respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC(0-∞)=142.8 vs. 147.0 adducts/10(6) nucleotidesh, respectively, p=0.59.

CONCLUSION

Overweight/obese patients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.

摘要

背景

环磷酰胺是一种烷化剂，在体内代谢激活为磷酰胺氮芥，形成有毒的 DNA-DNA（G-NOR-G）交联。环磷酰胺代谢物暴露增加与治疗相关的毒性有关。肥胖对环磷酰胺诱导的 G-NOR-G 交联暴露的影响尚不清楚。因此，我们试图确定肥胖是否会影响环磷酰胺特异性 G-NOR-G 交联的形成。

患者和方法

测量血浆中环磷酰胺浓度和血细胞核中 G-NOR-G 的含量。

结果

超重/肥胖患者接受的环磷酰胺日剂量明显较高（中位数 3000 与 4450mg，p<0.01）。尽管剂量较高，但超重/肥胖患者的环磷酰胺暴露量低于瘦患者，曲线下面积（AUC(0-∞））分别为 529.24 与 867.99μg/mlh，p<0.01。超重/肥胖患者与瘦患者的 G-NOR-G 含量相似，AUC(0-∞）分别为 142.8 与 147.0 加合物/10(6)核苷酸h，p=0.59。