期刊
ONCOTARGET
卷 5, 期 4, 页码 1062-1070出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1760
关键词
Rapamycin; Pemetrexed; Drug synergy; mTOR; Thymidylate Synthase; Lung Cancer
资金
- Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute
- Open Access Promotion Fund of the Johns Hopkins University Libraries
Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.
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