Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Via Gattamelata 64, Padua, Italy.
Cancer Chemother Pharmacol. 2013 Aug;72(2):483-8. doi: 10.1007/s00280-013-2210-1. Epub 2013 Jun 13.
5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities.
Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1).
Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association.
Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.
自 20 世纪 80 年代以来，5-氟尿嘧啶（5-FU）已被广泛应用，它仍然是许多化疗联合方案的基础。然而，其应用常因严重毒性的发生而受到限制。尽管有几项报告表明，一些二氢嘧啶脱氢酶（DPYD）和胸苷酸合成酶（TYMS）基因多态性在接受 5-FU 治疗的患者中具有有害影响，但它们仅占毒性的一小部分。
为了寻找与 5-FU 诱导的毒性相关的新候选遗传变异，我们使用了创新的基因分型微阵列 Affymetrix 药物代谢酶和转运体（DMET）™Plus GeneChip，该芯片检测了分布在参与药物代谢、排泄和转运的 231 个基因中的 1936 个遗传变异。为了减少变异性，我们分析了接受相当同质治疗（即 Machover 或 Folfox）并经历 G3 或 G4 毒性的结直肠癌患者的样本；对照患者按治疗进行匹配，并从未出现毒性（G0-G1）的患者中选择。
药物遗传学基因分型显示，病例和对照之间 DPYD 和 TYMS 基因变异分布无显著差异。然而，其他多态性可能导致 5-FU 诱导的毒性，其中 CHST1 rs9787901 和 GSTM3 rs1799735 具有最强的关联。
尽管这是一项探索性研究，但本研究表明，与 5-FU 药代动力学和药效学不直接相关的遗传多态性参与了 5-FU 诱导的毒性。我们的数据还表明，DMET™微阵列是发现影响化疗诱导毒性的新遗传决定因素的有效方法。
