College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Eur J Clin Pharmacol. 2012 Apr;68(4):389-95. doi: 10.1007/s00228-011-1134-0. Epub 2011 Oct 20.
The cytotoxic drug cyclophosphamide (CP) is bioactivated into 4-hydroxy-cyclophosphamide (4-OH-CP) through cytochrome P450 enzymes and cleared through aldehyde dehydrogenase and glutathione S-transferase. This prospective study analyzes the influence of drug metabolizing enzyme genotype on (1) plasma 4-OH-CP:CP ratio and (2) myelotoxicity in breast cancer patients on 500 mg/m(2) cyclophosphamide.
Sixty-eight female breast cancer patients on FAC (fluorouracil, adriamycin, cyclophosphamide) were included. Genotyping of cytochrome P450 enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5, aldehyde dehydrogenase (ALDH3A1), and glutathione S-transferase (GSTA1) was done either through RFLP or pyrosequencing. Plasma CP and 4-OH-CP were measured immediately and 1 and 2 h after the end of infusion through LC-MS. The leukocyte count was determined on day 10 and 20 after chemotherapy.
At CP dose of 500 mg/m(2), the 4-OH-CP:CP ratio was negatively affected by CYP2C192 genotype (p = 0.039) showing a gene-dose effect. Moreover ALDH3A12 genotype increased 4-OH-CP:CP ratio (p = 0.037). These effects did not remain significant in a univariate analysis of variance including all genotypes. GSTA1*B carriers were at increased risk of severe leucopenia (OR 6.94; 95% CI 1.75-27.6, p = 0.006).
The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.
细胞毒性药物环磷酰胺（CP）通过细胞色素 P450 酶生物转化为 4-羟基-环磷酰胺（4-OH-CP），并通过醛脱氢酶和谷胱甘肽 S-转移酶清除。本前瞻性研究分析了药物代谢酶基因型对（1）乳腺癌患者 500mg/m²环磷酰胺血浆 4-OH-CP：CP 比值和（2）骨髓抑制的影响。
纳入 68 例接受 FAC（氟尿嘧啶、阿霉素、环磷酰胺）治疗的女性乳腺癌患者。通过 RFLP 或焦磷酸测序对细胞色素 P450 酶 CYP2B6、CYP2C9、CYP2C19、CYP3A5、醛脱氢酶（ALDH3A1）和谷胱甘肽 S-转移酶（GSTA1）进行基因分型。通过 LC-MS 立即和输注结束后 1 和 2 小时测量血浆 CP 和 4-OH-CP。化疗后第 10 天和第 20 天测定白细胞计数。
在 CP 剂量为 500mg/m²时，CYP2C192 基因型（p=0.039）对 4-OH-CP：CP 比值呈负影响，表现出基因剂量效应。此外，ALDH3A12 基因型增加了 4-OH-CP：CP 比值（p=0.037）。在包括所有基因型的单因素方差分析中，这些影响并不显著。GSTA1*B 携带者发生严重白细胞减少的风险增加（OR 6.94；95%CI 1.75-27.6，p=0.006）。
接受 FAC 治疗的患者的骨髓抑制与 II 相酶 GSTA1 的活性有关，但与 4-OH-CP 的形成无关。
