Levy Adam S, Sather Harland N, Steinherz Peter G, Sowers Rebecca, La Mei, Moscow Jeffrey A, Gaynon Paul S, Uckun Fatih M, Bertino Joseph R, Gorlick Richard
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
J Pediatr Hematol Oncol. 2003 Sep;25(9):688-95. doi: 10.1097/00043426-200309000-00004.
Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome.
Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies.
Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance.
These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.
甲氨蝶呤是目前儿童急性淋巴细胞白血病（ALL）治疗方案的主要组成部分。甲氨蝶呤耐药的潜在机制包括药物摄取受损、药物潴留减少以及二氢叶酸还原酶（DHFR）扩增。本研究的目的是评估未经治疗的白血病原始细胞中叶酸转运体（RFC）和DHFR表达降低是否与预后相关。
采用定量实时RT-PCR检测40例新诊断ALL患者白血病原始细胞中RFC和DHFR mRNA表达，这些样本来自儿童癌症组研究，检测过程采用盲法。
诊断时RFC低表达与不良的无事件生存率显著相关。令人惊讶的是，低DHFR表达而非高DHFR表达与不良的无事件生存率显著相关。增殖细胞核抗原（PCNA）表达显示样本PCNA与DHFR或RFC表达之间呈弱负相关，提示DHFR和RFC表达可能是耐药以外因素的标志物。
这些结果表明，转运受损可能是ALL中甲氨蝶呤内在耐药的重要机制，DHFR表达也可能是ALL的重要预后因素。需要进一步研究以阐明低DHFR表达与不良预后相关的机制。
