Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
Blood. 2010 Jun 10;115(23):4671-7. doi: 10.1182/blood-2010-01-256958. Epub 2010 Mar 24.
The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G>A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.
还原叶酸载体（RFC）参与甲氨蝶呤（MTX）穿过细胞膜的转运。RFC 基因（SLC19A1）位于 21 号染色体上，我们假设 RFC80G>A 多态性会影响儿童白血病的结局和毒性，并且这种影响可能与白血病克隆中的 21 号染色体拷贝数相互作用。共纳入 500 例按照北欧常见治疗方案治疗的急性淋巴细胞白血病患儿，我们发现与 GG 或 GA 变异型相比，RFCAA 变异型有 50%更好的缓解机会（P=.046）。21 号染色体拷贝数的增加似乎也改善了 GA 或 GG 变异型患儿的结局。在接受 608 个高剂量 MTX 疗程的 182 例患儿亚组中，我们观察到与 GA/GG 变异型相比，RFCAA 变异型患者的骨髓毒性程度更高（血小板 73 与 99/105×10(9)/L，P=.004，血红蛋白 5.6 与 5.9/6.0mmol/L，P=.004），而 RFCGG 变异型患者的肝毒性程度更高（丙氨酸氨基转移酶 167 与 127/124U/L，P=.05）。总之，RFC80G>A 多态性与 21 号染色体拷贝数相互作用，影响 MTX 的疗效和毒性。
