Beneficial effect of metronomic chemotherapy on tumor suppression and survival in a rat model of hepatocellular carcinoma with liver cirrhosis

• Published in: Cancer chemotherapy and pharmacology Vol. 65; no. 6; pp. 1029 - 1037
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.05.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Body Weight - drug effects; Cancer Research; Cell Proliferation - drug effects; Cyclophosphamide - administration & dosage; Cyclophosphamide - therapeutic use; Diethylnitrosamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Immunoblotting; Kaplan-Meier Estimate; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - drug therapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Other diseases. Semiology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Proliferating Cell Nuclear Antigen - metabolism; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Tumor Burden - drug effects; Tumors; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; von Willebrand Factor - metabolism; Angiogenesis; Hepatocellular carcinoma; Cyclophosphamide; Metronomic chemotherapy; Antineoplastic agent; Animal model; Rat; Digestive system; Liver; Rodentia; Hepatic disease; Malignant tumor; Survival; Liver cancer; Cirrhosis; Alkylating agent; Oxazaphosphinane derivatives; Vertebrata; Mammalia; Nitrogen mustard; Digestive diseases; Neovascularization; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-009-1108-4

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.