title: Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat model of hepatocellular carcinoma.
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-1α 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.
authors.affiliation: Department of Internal Medicine, WHO Collaborating for Reference Research on Viral Hepatitis.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Jang
authors.forename: Seong Tae
authors.initials: ST
authors.lastname: Park
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Kwon
authors.forename: Chan Ran
authors.initials: CR
authors.lastname: You
authors.forename: Jong Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Jung
authors.forename: Si Hyun
authors.initials: SH
authors.lastname: Bae
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000494:pharmacology*; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000139:chemically induced; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019714:Tissue Inhibitor of Metalloproteinases; D004052:Diethylnitrosamine; D003520:Cyclophosphamide; D020782:Matrix Metalloproteinases