Exp Mol Med.  2011 May;43(5):305-312. 10.3858/emm.2011.43.5.033.

Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat model of hepatocellular carcinoma

• Jang JW
• Park ST
• Kwon JH
• You CR
• Choi JY
• Jung CK
• Bae SH
• Yoon SK

• KMID: 1009970
• DOI: http://doi.org/10.3858/emm.2011.43.5.033

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.

Keyword

cyclophosphamide; hepatocellular carcinoma; metastasis; metronomic chemotherapy

MeSH Terms

Animals
Antineoplastic Agents/*administration & dosage/*pharmacology
Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology
Cell Proliferation/drug effects
Cyclophosphamide/*administration & dosage/*pharmacology
Diethylnitrosamine
Disease Models, Animal
Gene Expression Regulation, Neoplastic/*drug effects
Liver Cirrhosis/chemically induced
Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology
Lung Neoplasms/drug therapy/pathology/secondary
Male
Matrix Metalloproteinases/metabolism
Neovascularization, Pathologic/enzymology/physiopathology
Rats
Rats, Sprague-Dawley
Survival Analysis
Tissue Inhibitor of Metalloproteinases/metabolism
Tumor Burden/drug effects