Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat model of hepatocellular carcinoma
Experimental & Molecular Medicine
;
: 305-312, 2011.
Article
in English
| WPRIM
| ID: wpr-168746
ABSTRACT
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Gene Expression Regulation, Neoplastic
/
Survival Analysis
/
Rats, Sprague-Dawley
/
Carcinoma, Hepatocellular
/
Tissue Inhibitor of Metalloproteinases
/
Matrix Metalloproteinases
/
Cyclophosphamide
/
Tumor Burden
/
Cell Proliferation
/
Diethylnitrosamine
Type of study:
Prognostic study
Limits:
Animals
Language:
English
Journal:
Experimental & Molecular Medicine
Year:
2011
Type:
Article
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