mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia

被引：95

作者：

Teachey, David T. ^{[1
]}

Sheen, Cecilia ^{[1
]}

Hall, Junior ^{[1
]}

Ryan, Theresa ^{[1
]}

Brown, Valerie I. ^{[1
]}

Fish, Jonathan ^{[1
]}

Reid, Gregor S. D. ^{[1
]}

Seif, Alix E. ^{[1
]}

Norris, Robin ^{[1
]}

Chang, Yueh J. ^{[1
]}

Carroll, Martin ^{[3
]}

Grupp, Stephan A. ^{[1
,2
]}

机构：

[1] Childrens Hosp, Div Oncol, Dept Pediat, Philadelphia, PA 19104 USA

[2] Childrens Hosp, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA

来源：

BLOOD | 2008年 / 112卷 / 05期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1182/blood-2008-02-137141

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 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 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.

引用

页码：2020 / 2023

页数：4

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