Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Pediatr Blood Cancer. 2012 May;58(5):708-14. doi: 10.1002/pbc.23254. Epub 2011 Jul 25.
Fanconi anemia (FA) patients are hypersensitive to DNA alkylating agents and require lower doses than non-FA patients to minimize serious toxicity. The mechanism by which hypersensitivity occurs is thought to be due to the inability of these individuals to effectively repair drug-induced interstrand DNA-DNA crosslinks. We recently developed a highly sensitive assay for cyclophosphamide specific interstrand DNA-DNA crosslinks (G-NOR-G) and are able to quantify and compare formation of these adducts in the blood of patients. Therefore we sought to determine whether FA patients have higher in vivo exposure to the cyclophosphamide specific interstrand DNA crosslink, G-NOR-G, relative to patients without FA.
Cyclophosphamide interstrand DNA crosslinks were measured with the first dose of cyclophosphamide in FA and non-FA patients receiving a cyclophosphamide based preparative regimen prior to hematopoietic cell transplantation (HCT). FA patients received a lower cyclophosphamide dose than the non-FA patients (5-10 mg/kg/day vs. 50-60 mg/kg/day).
Despite the lower cyclophosphamide dose and lower plasma concentrations in FA patients, they had G-NOR-G amounts similar to the non-FA patients (area under the curve (AUC)(0-∞) , 99.8 vs. 144.9 G-NOR-G adducts/10(6) nucleotides hour, respectively, P = 0.47). When G-NOR-G AUC was normalized for cyclophosphamide plasma concentrations, FA study subjects produced 15-fold higher adducts than non-FA patients (P = 0.05).
FA patients are hypersensitive to DNA alkylating agents possibly as a result of greater formation of cyclophosphamide specific interstrand DNA crosslinks and/or diminished capacity for DNA repair. Identification and quantification of these adducts may be important determinant of cyclophosphamide related toxicity.
范可尼贫血（FA）患者对 DNA 烷化剂敏感，需要比非 FA 患者更低的剂量，以最大限度地减少严重毒性。认为这种敏感性发生的机制是由于这些个体无法有效修复药物诱导的链间 DNA-DNA 交联。我们最近开发了一种用于检测环磷酰胺特异性链间 DNA-DNA 交联（G-NOR-G）的高度敏感测定法，并能够定量和比较这些加合物在患者血液中的形成。因此，我们试图确定 FA 患者相对于没有 FA 的患者，体内是否有更高的环磷酰胺特异性链间 DNA 交联，G-NOR-G 暴露。
在接受基于环磷酰胺的预处理方案以进行造血细胞移植（HCT）之前，FA 和非 FA 患者在接受环磷酰胺的第一剂量时，用该方法测量环磷酰胺链间 DNA 交联。FA 患者接受的环磷酰胺剂量低于非 FA 患者（5-10 mg/kg/天与 50-60 mg/kg/天）。
尽管 FA 患者的环磷酰胺剂量较低且血浆浓度较低，但他们的 G-NOR-G 量与非 FA 患者相似（曲线下面积（AUC）（0-∞）分别为 99.8 和 144.9 G-NOR-G 加合物/10（6）核苷酸小时，P = 0.47）。当将 G-NOR-G AUC 标准化为环磷酰胺血浆浓度时，FA 研究对象产生的加合物比非 FA 患者高 15 倍（P = 0.05）。
FA 患者对 DNA 烷化剂敏感，可能是由于形成了更多的环磷酰胺特异性链间 DNA 交联和/或 DNA 修复能力下降。这些加合物的鉴定和定量可能是环磷酰胺相关毒性的重要决定因素。
