Influence of Genetic Variation of GST, CYP, and ABC on the Safety and Efficacy of Cyclophosphamide-Based Therapy

Abstract

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. CYP2C19*2 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 CYP2C19*2, 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.