期刊
BLOOD
卷 112, 期 5, 页码 2020-2023出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-02-137141
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类别
资金
- National Institutes of Health (Bethesda, MD) [CA102646, CA1116660, ACG RSG0507101]
- Sanford Chair of the Children's Hospital of Philadelphia
- Leukemia & Lymphoma Society
- ASCO
- Young Investigator and Career Development Awards
- Larry and Helen Hoag Foundation
- Clinical Translational Research Scientist Award
- NATIONAL CANCER INSTITUTE [R01CA102646, K08CA104882] Funding Source: NIH RePORTER
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.
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