背景:细胞色素P450(CYP)是参与化学治疗剂解毒的I期代谢酶。在CYP基因家族中,包括CYP1A1,CYP1B1,CYP2C,CYP2D,CYP2E和CYP17,它们在癌症易感性中的意义已得到充分证实。然而,对于CYP2C19*2和CYP17的多态性及其与乳腺癌(BC)患者化疗诱导的毒性反应的潜在相关性的认识仍然有限.在这项研究中,我们旨在确定CYP2C19*2和CYP17基因多态性与印度人群中接受阿霉素/紫杉醇化疗的BC患者的药物反应和毒性反应的关系。
方法:本研究纳入接受阿霉素和紫杉醇化疗的200例BC患者,观察化疗引起的血液学和非血液学毒性反应。通过PCR和RFLP分析研究了细胞色素p450基因CYP2C19*2(681G>A)和CYP17(34T>C)亚型的多态性。
结果:单变量逻辑回归分析显示CYP2C19*2(681G>A)多态性与血液学毒性之间存在显着关联,即贫血(OR=9.77,95%CI:2.84-33.52;p=0.0003),中性粒细胞减少症(OR=5.72,95%CI:1.75-18.68;p=0.003),BC患者发热性中性粒细胞减少(OR=4.29,95%CI:1.32-13.87;p=0.014)和血小板减少(OR=5.86,95%CI:1.15-29.72;p=0.032)。此外,接受阿霉素治疗的BC患者CYP2C19*2多态性与化疗引起的恶心和呕吐(CINV)之间存在显着关联(OR=99.73,95%CI:5.70-174.64);p=0.001,疲劳(OR=83.29,95%CI:4.77-145.69);p=0.002),疼痛(OR=4.44,95%CI:1.24-15.91);p=0.021)和周围神经病变(OR=12.00,95%CI:1.80-79.89);p=0.010。此外,回归分析显示,在接受紫杉醇化疗的BC患者中,CYP17与身体疼痛(OR=2.77,95%CI:1.21~6.34;p=0.015)和周围神经病变(OR=3.90,95%CI:1.59~9.53;p=0.002)之间存在相关性.
结论:从这项研究中获得的发现表明,CYP2C9*2(681G>A)多态性与基于阿利霉素的化疗诱导的毒性反应以及CYP17(34T>C)多态性与紫杉醇诱导的身体疼痛和周围神经病变密切相关。
BACKGROUND: Cytochrome P450 (CYP) are phase I metabolizing enzymes involved in detoxification of chemotherapeutic agents. Among the CYP gene family, including CYP1A1, CYP1B1, CYP2C, CYP2D, CYP2E and CYP17, their significance in cancer susceptibility is well established. However, there remains limited understanding regarding the polymorphisms of
CYP2C19*2 and CYP17 and their potential correlation with chemotherapy-induced toxicity reactions in breast cancer (BC) patients. In this study we intended to identify the association of
CYP2C19*2 and CYP17 gene polymorphisms on drug response as well as toxicity reactions in BC patients undergoing adriamycin/paclitaxel based chemotherapy within Indian population.
METHODS: Two hundred BC patients receiving adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms of
CYP2C19*2 (681G>A) and CYP17 (34T>C) isoforms of cytochrome p 450 gene was studied by PCR and RFLP analysis.
RESULTS: The univariate logistic regression analysis revealed significant associations between
CYP2C19*2 (681 G>A) polymorphisms with hematological toxicities i.e., anemia (OR=9.77, 95% CI: 2.84-33.52; p=0.0003), neutropenia (OR=5.72, 95% CI: 1.75-18.68; p=0.003), febrile neutropenia (OR=4.29, 95% CI: 1.32-13.87; p=0.014) and thrombocytopenia (OR=5.86, 95% CI: 1.15-29.72); p=0.032) in BC patients. Additionally BC patients treated with adriamycin exhibited significant association between
CYP2C19*2 polymorphism with chemotherapy induced nausea and vomiting (CINV) (OR=99.73, 95% CI: 5.70-174.64); p=0.001), fatigue (OR=83.29, 95% CI: 4.77-145.69); p=0.002), bodyache (OR=4.44, 95% CI: 1.24-15.91); p=0.021) and peripheral neuropathy (OR=12.00, 95% CI: 1.80-79.89); p=0.010. Furthermore, the regression analysis indicated an association between CYP17 with body ache (OR=2.77, 95% CI: 1.21-6.34; p=0.015) and peripheral neuropathy (OR=3.90, 95% CI: 1.59-9.53; p=0.002) in BC patients treated with paclitaxel chemotherapy.
CONCLUSIONS: The findings obtained from this study illustrated significant association of CYP2C9*2 (681G>A) polymorphism with adreamicin based chemotherapy induced toxicities and CYP17 (34T>C) polymorphism with paclitaxel induced bodyache and peripheral neuropathy in BC patients.