Molecular and cellular correlates of methotrexate response in childhood acute lymphoblastic leukemia.
Molecular and cellular correlates of methotrexate response in childhood acute lymphoblastic leukemia.
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DOI：
10.3109/10428199909145701
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发表时间：
1999-09
影响因子：
2.6
通讯作者：
L. Matherly;J. Taub
中科院分区：
文献类型：
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作者：
L. Matherly;J. Taub
与40年前相比，今天诊断为急性淋巴细胞白血病（ALL）的儿童的前景有所改善。通过现代疗法和支持性护理，高达95%的患者实现了完全缓解，长期无病生存率接近80%。甲氨蝶呤是急性淋巴细胞白血病巩固和维持治疗的关键组成部分，用于预防和治疗中枢神经系统白血病的鞘内注射。最近的报告大大扩展了甲氨蝶呤对ALL患者的反应和耐药性的临床前研究结果。新的和敏感的分子生物学技术的应用使得研究特定的染色体和遗传改变[t(12;21)，高二倍体，p15INK4B和p16INK4A的缺失或甲基化]成为可能，这些改变可能有助于儿童ALL的甲氨蝶呤反应和耐药性。对遗传改变与ALL进展、甲氨蝶呤药理学和长期无事件生存之间关系的研究，可能有助于更好地识别对包括甲氨蝶呤在内的化疗具有独特敏感性或耐药性的患者亚组。此外，通过表征易位产生的融合基因（TEL-AML 1）和肿瘤抑制基因（p15INK4B和p16INK4A）在治疗反应中的作用，可能有可能为目前治疗难治性ALL的儿童和成人确定新的选择性靶点和/或治疗策略。
The improved outlook for children diagnosed today with acute lymphoblastic leukemia (ALL) over that 40 years ago is remarkable. With modern therapies and supportive care, complete remissions are achieved in up to 95% of patients and long-term disease-free survival rates approach 80%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Recent reports have significantly extended the results of preclinical studies of methotrexate response and resistance to patients with ALL. The application of new and sensitive molecular biology techniques makes it possible to study specific chromosomal and genetic alterations [t(12;21), hyperdiploidy, deletions or methylation of p15INK4B and p16INK4A] which potentially contribute to methotrexate response and resistance in childhood ALL. Studies of the relationships between genetic alterations and ALL progression, methotrexate pharmacology, and long term event-free-survivals may lead to the better identification of subgroups of patients who exhibit unique levels of sensitivity or resistance to chemotherapy including methotrexate. Further, by characterizing the roles of translocation-generated fusion genes (TEL-AML 1) and tumor suppressor genes (p15INK4B and p16INK4A) in treatment response, it may be possible to identify new and selective targets and/or treatment strategies for both children and adults with ALL who are refractory to current therapies.