Teachey David T, Sheen Cecilia, Hall Junior, Ryan Theresa, Brown Valerie I, Fish Jonathan, Reid Gregor S D, Seif Alix E, Norris Robin, Chang Yueh J, Carroll Martin, Grupp Stephan A
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA.
Blood. 2008 Sep 1;112(5):2020-3. doi: 10.1182/blood-2008-02-137141. Epub 2008 Jun 10.
We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of acute lymphoblastic leukemia (ALL). MTIs may increase degradation of cyclin D1, a protein involved in dihydrofolate reductase (DHFR) synthesis. Because resistance to methotrexate may correlate with high DHFR expression, we hypothesized MTIs may increase sensitivity of ALL to methotrexate through decreasing DHFR by increasing turn-over of cyclin D1. We tested this hypothesis using multiple ALL cell lines and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with human ALL. We found MTIs and methotrexate were synergistic in combination in vitro and in vivo. Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed. ALL cells treated with MTIs had markedly decreased expression of DHFR and cyclin D1, providing a novel mechanistic explanation for a combined effect. We found methotrexate and MTIs are an effective and potentially synergistic combination in ALL.
我们之前已经证明，雷帕霉素靶蛋白（mTOR）抑制剂（MTIs）在急性淋巴细胞白血病（ALL）的临床前模型中具有活性。MTIs可能会增加细胞周期蛋白D1的降解，细胞周期蛋白D1是一种参与二氢叶酸还原酶（DHFR）合成的蛋白质。由于对甲氨蝶呤的耐药性可能与高DHFR表达相关，我们推测MTIs可能通过增加细胞周期蛋白D1的周转来降低DHFR，从而增加ALL对甲氨蝶呤的敏感性。我们使用多种ALL细胞系以及移植了人ALL的非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠来验证这一假设。我们发现MTIs和甲氨蝶呤在体外和体内联合使用时具有协同作用。接受两种药物治疗的小鼠实现了完全且持久的缓解，而单药治疗则导致了最初的部分缓解，但最终病情进展。用MTIs处理的ALL细胞中DHFR和细胞周期蛋白D1的表达明显降低，这为联合用药的效果提供了一种新的机制解释。我们发现甲氨蝶呤和MTIs在ALL中是一种有效且可能具有协同作用的联合用药方案。
