Yao Zhong-Wei, Li Qi-Long, Hu Wei-Feng, Pan Ling-Hui, Wu Jun-Wen, Ren Wen-Lu, Jia Hui-Tian, Wang Pan-Pan, Fu Zhi-Ying, Zhu He
Drug Clinical Trial Center, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
Clin Transl Sci. 2025 Jul;18(7):e70301. doi: 10.1111/cts.70301.
Cyclophosphamide (CTX) is one of the most widely used drugs in the clinical treatment of tumors and autoimmune diseases. The correlation between CYP, GST, and ABC gene polymorphisms and CTX activity and its induced toxicity has been extensively studied, but with inconsistent conclusions. In this study, a meta-analysis protocol was employed to comprehensively evaluate the relationship between the gene polymorphisms, including CYP2C9, CYP2C19, CYP2B6, CYP3A5, GSTA1, GSTM1, GSTT1, GSTP1, ABCB1, ABCC4, and ABCG2, and the safety and efficacy of CTX. Forty-five eligible literatures were retrieved from PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases. The results showed that CYP, GST, and ABC gene polymorphisms analyzed in the study were not associated with the efficacy but related to the safety of CTX. CYP2C192 polymorphism showed low risk with CTX-induced gastrointestinal toxicity (RR, 3.70; 95% CI, 1.60-8.55; p = 0.002). The GSTT1-present genotype showed low risk with hematological (RR, 0.63; 95% CI, 0.42-0.96; p = 0.03), gastrointestinal toxicity (RR, 0.62; 95% CI, 0.41-0.94; p = 0.02) and other toxicities (RR, 0.60; 95% CI, 0.38-0.97; p = 0.04). The GSTP1 (rs1695) wild-type showed low risk with gastrointestinal toxicity (RR, 0.69; 95% CI, 0.52-0.92; p = 0.01). Additionally, the ABCC4 (rs9561778) wild-type also showed low risk with gastrointestinal toxicity (RR, 0.50; 95% CI, 0.28-0.88; p = 0.02). Our findings confirm that the polymorphisms of CYP2C192, GSTT1, GSTP1 (rs1695), and ABCC4 (rs9561778) play an important role in predicting the risk of hematological, gastrointestinal, and other toxicities in patients undergoing CTX treatment.
环磷酰胺（CTX）是肿瘤和自身免疫性疾病临床治疗中应用最广泛的药物之一。细胞色素P450酶系（CYP）、谷胱甘肽S-转移酶（GST）和ATP结合盒（ABC）基因多态性与CTX活性及其诱导的毒性之间的相关性已得到广泛研究，但结论不一致。本研究采用荟萃分析方案，全面评估包括CYP2C9、CYP2C19、CYP2B6、CYP3A5、GSTA1、GSTM1、GSTT1、GSTP1、ABCB1、ABCC4和ABCG2在内的基因多态性与CTX安全性和疗效之间的关系。从PubMed、Web of Science、Embase和中国知网（CNKI）数据库中检索到45篇符合条件的文献。结果表明，本研究中分析的CYP、GST和ABC基因多态性与CTX疗效无关，但与安全性有关。CYP2C192基因多态性与CTX诱导的胃肠道毒性风险较低相关（相对危险度[RR]，3.70；95%置信区间[CI]，1.60 - 8.55；p = 0.002）。GSTT1存在型基因型与血液学毒性（RR，0.63；95% CI，0.42 - 0.96；p = 0.03）、胃肠道毒性（RR，0.62；95% CI，0.41 - 0.94；p = 0.02）及其他毒性（RR，0.60；95% CI，0.38 - 0.97；p = 0.04）风险较低相关。GSTP1（rs1695）野生型与胃肠道毒性风险较低相关（RR，0.69；95% CI，0.52 - 0.92；p = 0.01）。此外，ABCC4（rs9561778）野生型也与胃肠道毒性风险较低相关（RR，0.50；95% CI，0.28 - 0.88；p = 0.02）。我们的研究结果证实，CYP2C192、GSTT1、GSTP1（rs1695）和ABCC4（rs9561778）基因多态性在预测接受CTX治疗患者的血液学、胃肠道及其他毒性风险方面发挥重要作用。
