PMID- 20960030
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20220317
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 30
IP  - 1
DP  - 2012 Feb
TI  - Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the 
      mTOR inhibitor everolimus and anticancer drugs.
PG  - 223-35
LID - 10.1007/s10637-010-9558-4 [doi]
AB  - 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.
FAU - Huang, Jia-Jia
AU  - Huang JJ
AD  - Department of Medical Oncology, Cancer Center, Sun Yat-sen University, 651, 
      Dongfeng Road East, Guangzhou, Guangdong 510060, People's Republic of China.
FAU - Li, Zhi-Ming
AU  - Li ZM
FAU - Huang, Ying
AU  - Huang Y
FAU - Huang, Yan
AU  - Huang Y
FAU - Tian, Ying
AU  - Tian Y
FAU - He, Xue-Xin
AU  - He XX
FAU - Xiao, Jian
AU  - Xiao J
FAU - Lin, Tong-Yu
AU  - Lin TY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101020
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Boronic Acids)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazines)
RN  - 5J49Q6B70F (Vincristine)
RN  - 69G8BD63PP (Bortezomib)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 80168379AG (Doxorubicin)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Doxorubicin/pharmacology
MH  - Drug Synergism
MH  - Etoposide/pharmacology
MH  - Everolimus
MH  - Humans
MH  - Jurkat Cells
MH  - Lymphoma, T-Cell/*enzymology/pathology
MH  - PTEN Phosphohydrolase/metabolism
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrazines/pharmacology
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Time Factors
MH  - Vincristine/pharmacology
EDAT- 2010/10/21 06:00
MHDA- 2012/05/09 06:00
CRDT- 2010/10/21 06:00
PHST- 2010/08/09 00:00 [received]
PHST- 2010/09/29 00:00 [accepted]
PHST- 2010/10/21 06:00 [entrez]
PHST- 2010/10/21 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
AID - 10.1007/s10637-010-9558-4 [doi]
PST - ppublish
SO  - Invest New Drugs. 2012 Feb;30(1):223-35. doi: 10.1007/s10637-010-9558-4. Epub 
      2010 Oct 20.