Park, Seong Tae; Jang, Jeong Won; Kim, Gi Dae; Park, Joung Ah; Hur, Wonhee; Woo, Hyun Young; Kim, Jin Dong; Kwon, Jeong Hyun; Yoo, Chan Ran; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew
Cancer chemotherapy and pharmacology
2010May ; 65 ( 6 ) :1029-37.
PMID : 19701751
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Park, Seong Tae -
Jang, Jeong Won -
Kim, Gi Dae -
Park, Joung Ah -
Hur, Wonhee -
Woo, Hyun Young -
Kim, Jin Dong -
Kwon, Jeong Hyun -
Yoo, Chan Ran -
Bae, Si Hyun -
Choi, Jong Young -
Yoon, Seung Kew -
ABSTRACT
PURPOSE: Recent studies have demonstrated that frequent, low-dose metronomic (MET) dosing of cytotoxic agents may not only be as efficient as conventional maximum tolerated dose (MTD) chemotherapy but also less toxic. In this study, we investigated the therapeutic effect and safety of MET chemotherapy using cyclophosphamide (CTX) in rats with chemically induced hepatocellular carcinoma (HCC).
METHODS: Rats received weekly intraperitoneal (i.p.) injections of diethylnitrosamine during 16 weeks for induction of HCC. The rats were divided into three groups: MTD group received 40 mg/kg CTX i.p. injection on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received saline and 20 mg/kg CTX i.p. injection twice a week, respectively. The growth-modulating effects and overall survival were compared between the groups. Anti-angiogenic effects were evaluated by a measurement of endothelial cell and VEGFR-2 expression.
RESULTS: At 6 weeks of therapy, MTD and MET chemotherapy resulted in a significant reduction in tumor number and size compared with Control group. MET chemotherapy showed more prolonged survival than MTD chemotherapy and Control groups (P < 0.05). MET chemotherapy resulted in a significant decrease in both the micro-vessel density and endothelial proliferation index (P < 0.01). Furthermore, MET chemotherapy led to a greater decrease in VEGFR-2 expression at the mRNA and protein levels (P < 0.01).
CONCLUSIONS: MET scheduling not only exhibits anti-tumor and anti-angiogenic effects, but also prolongs survival without major toxicities in a rat model of HCC. Our results suggest that MET chemotherapy has a high therapeutic value and should be considered for future clinical trials.
Hepatocellular carcinoma, Metronomic chemotherapy, Cyclophosphamide, Angiogenesis
MESH
Animals, Antineoplastic Agents, Alkylating/administration & dosage/therapeutic use, Apoptosis/drug effects, Body Weight/drug effects, Cell Proliferation/drug effects, Cyclophosphamide/administration & dosage/*therapeutic use, Diethylnitrosamine, Dose-Response Relationship, Drug, Drug Administration Schedule, Endothelial Cells/cytology/drug effects/metabolism, Immunoblotting, Kaplan-Meier Estimate, Liver/*drug effects/metabolism/pathology, Liver Cirrhosis/chemically induced/*drug therapy, Liver Neoplasms, Experimental/chemically induced/*drug therapy, Proliferating Cell Nuclear Antigen/metabolism, Random Allocation, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Tumor Burden/drug effects, Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism, von Willebrand Factor/metabolism
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