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Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs.
MedLine Citation:
PMID:  20960030     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Objective Everolimus (RAD001) is a novel mammalian target of rapamycin (mTOR) inhibitor, and anti-proliferative activity in various malignancies has been reported. This study evaluated the anti-tumor effects and schedule-dependent synergism of everolimus in combination with other chemotherapeutic agents in T-cell lymphoma cell lines. Materials and methods Human T-cell lymphoma cell lines Hut-78 and Jurkat were treated with increasing doses of everolimus, alone or in combination with doxorubicin, etoposide, vincristine, or bortezomib, using different dosing schedules. Anti-tumor effects were measured by assays for cell proliferation, apoptosis, and cell cycle distribution. Drug interactions were determined by median effect analysis. Results Exposure to everolimus alone induced G1 phase cell cycle arrest without significant apoptosis. With certain dosing schedules, everolimus showed synergism with doxorubicin, etoposide, and bortezomib, but antagonism with vincristine. Cytotoxic synergism was observed following cotreatment with doxorubicin and everolimus, bortezomib and everolimus, doxorubicin followed by everolimus, and bortezomib followed by everolimus. By contrast, cell exposure to everolimus followed by doxorubicin or followed by bortezomib resulted in antagonistic effects. Sequential exposure to doxorubicin or bortezomib followed by everolimus effectively prevented potential negative interactions, and resulted in drug synergism. Drug combination synergisms or antagonisms were associated with variable effects on the cell cycle distribution. Conclusions Everolimus effectively inhibited the growth of T-cell lymphoma cells in vitro. Specific schedule-dependent combinations of everolimus with other anti-tumor agents which avoid potential drug antagonism and produce effective synergism may lead to clinically effective treatments for T-cell lymphoma.
Authors:
Jia-Jia Huang; Zhi-Ming Li; Ying Huang; Yan Huang; Ying Tian; Xue-Xin He; Jian Xiao; Tong-Yu Lin
Publication Detail:
Type:  Journal Article     Date:  2010-10-20
Journal Detail:
Title:  Investigational new drugs     Volume:  30     ISSN:  1573-0646     ISO Abbreviation:  Invest New Drugs     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8309330     Medline TA:  Invest New Drugs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  223-35     Citation Subset:  IM    
Affiliation:
Department of Medical Oncology, Cancer Center, Sun Yat-sen University, 651, Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China.
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