PMID- 21483229
OWN - NLM
STAT- MEDLINE
DCOM- 20111003
LR  - 20211020
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 43
IP  - 5
DP  - 2011 May 31
TI  - Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat 
      model of hepatocellular carcinoma.
PG  - 305-12
LID - 10.3858/emm.2011.43.5.033 [doi]
AB  - Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer 
      efficacy in various cancer models, the effect of long-term MET therapy for 
      hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term 
      efficacy of MET on suppression of tumor growth and spontaneous metastasis in a 
      rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The 
      rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) 
      injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; 
      Control and MET groups received i.p. injections of saline and 20 mg/kg 
      cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic 
      effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) 
      and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy 
      resulted in a significant reduction in intrahepatic tumors than control or MTD 
      therapy. The MET group had fewer proliferating cell nuclear antigen-positive 
      cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. 
      Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and 
      MET groups, respectively. MET therapy significantly decreased expression of 
      TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced 
      significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET 
      group was significantly prolonged compared to the control and MTD groups. 
      Long-term MET scheduling suppresses tumor growth and metastasis via its potent 
      anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These 
      results provide a rationale for long-term MET dosing in future clinical trials of 
      HCC treatment.
FAU - Jang, Jeong Won
AU  - Jang JW
AD  - Department of Internal Medicine, WHO Collaborating for Reference Research on 
      Viral Hepatitis.
FAU - Park, Seong Tae
AU  - Park ST
FAU - Kwon, Jung Hyun
AU  - Kwon JH
FAU - You, Chan Ran
AU  - You CR
FAU - Choi, Jong Young
AU  - Choi JY
FAU - Jung, Chan Kwon
AU  - Jung CK
FAU - Bae, Si Hyun
AU  - Bae SH
FAU - Yoon, Seung Kew
AU  - Yoon SK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/*pharmacology
MH  - Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology
MH  - Cell Proliferation/drug effects
MH  - Cyclophosphamide/*administration & dosage/*pharmacology
MH  - Diethylnitrosamine
MH  - Disease Models, Animal
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Liver Cirrhosis/chemically induced
MH  - Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology
MH  - Lung Neoplasms/drug therapy/pathology/secondary
MH  - Male
MH  - Matrix Metalloproteinases/metabolism
MH  - Neovascularization, Pathologic/enzymology/physiopathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Survival Analysis
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
MH  - Tumor Burden/drug effects
PMC - PMC3104253
EDAT- 2011/04/13 06:00
MHDA- 2011/10/04 06:00
PMCR- 2011/05/31
CRDT- 2011/04/13 06:00
PHST- 2011/04/13 06:00 [entrez]
PHST- 2011/04/13 06:00 [pubmed]
PHST- 2011/10/04 06:00 [medline]
PHST- 2011/05/31 00:00 [pmc-release]
AID - emm.2010.43.033 [pii]
AID - 10.3858/emm.2011.43.5.033 [doi]
PST - ppublish
SO  - Exp Mol Med. 2011 May 31;43(5):305-12. doi: 10.3858/emm.2011.43.5.033.