Marangoni-Iglecias Luciana Maria, Sánchez-Martin Almudena, Pineda-Lancheros Laura Elena, Cura Yasmín, Marquez-Pete Noelia, Gálvez-Navas José María, Báez-Gutiérrez Nerea, Jara-Vera Adrián Manuel de La, Urrutia-Maldonado Emilia, Pérez-Ramírez Cristina, Jiménez-Morales Alberto
Clinical Analysis Laboratory Unit, Hospital Universitário Maria Aparecida Pedrossian HUMAP-UFMS. Av. Sen. Filinto Müler, 355-Vila Ipiranga, Campo Grande 79080-190, Brazil.
Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain.
Pharmaceutics. 2025 Apr 29;17(5):585. doi: 10.3390/pharmaceutics17050585.
: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. Multivariate logistic regression analysis revealed that the male sex ( = 0.3) and the AA genotype of rs2236225 were associated with grade III-IV gastrointestinal toxicity ( = 0.03), while the A allele of rs1801133 and the AA genotype of rs1695 were associated with grade I-IV hematologic toxicity ( < 0.01 and = 0.02, respectively). High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.
儿童癌症是一组异质性恶性肿瘤，仍然是14岁以下儿童死亡的主要原因之一，仅次于意外伤害，在15至19岁人群中排第四。尽管治愈率有显著提高，但相当一部分患者经历与治疗相关的急性或长期毒性。甲氨蝶呤（MTX）作为一种化疗药物，已在儿科恶性肿瘤治疗中有效应用了六十多年。大剂量甲氨蝶呤是儿科癌症治疗的基石；然而，其临床应用常常受到剂量限制性毒性的限制。本研究调查参与核苷酸代谢以及甲氨蝶呤和叶酸代谢途径的基因中的遗传多态性对儿童癌症治疗相关毒性的影响。使用实时聚合酶链反应，对107名患者队列中的12个基因的14种多态性进行了分析。根据不良事件通用术语标准第5.0版评估毒性。多变量逻辑回归分析显示，男性（比值比 = 0.3）和rs2236225的AA基因型与III - IV级胃肠道毒性相关（比值比 = 0.03），而rs1801133的A等位基因和rs1695的AA基因型与I - IV级血液学毒性相关（分别为比值比 < 0.01和比值比 = 0.02）。大剂量甲氨蝶呤（HDMTX）是儿童癌症治疗中的关键药物。我们的研究结果表明，甲氨蝶呤和叶酸代谢途径中的遗传多态性可能作为治疗相关毒性的潜在预测生物标志物。
