Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 6, pp 1029–1037 | Cite as

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

  • Seong Tae Park
  • Jeong Won Jang
  • Gi Dae Kim
  • Joung Ah Park
  • Wonhee Hur
  • Hyun Young Woo
  • Jin Dong Kim
  • Jeong Hyun Kwon
  • Chan Ran Yoo
  • Si Hyun BaeEmail author
  • Jong Young Choi
  • Seung Kew Yoon
Original Article



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).


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.


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).


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 



Hepatocellular carcinoma


Maximum tolerated dose




Vascular endothelial growth factor






Proliferating cell nuclear antigen


von-Willebrand factor


Reverse transcription-polymerase chain reaction


Polyacylamide gel electrophoresis



This research was supported by The Korean Association for the Study of the Liver, grant no. 0620390 from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea, and the second stage of Brain Korea 21 project.

Conflict of interest statement

There are no conflicts of interest in this work.


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Seong Tae Park
    • 1
  • Jeong Won Jang
    • 2
  • Gi Dae Kim
    • 1
  • Joung Ah Park
    • 1
  • Wonhee Hur
    • 1
  • Hyun Young Woo
    • 2
  • Jin Dong Kim
    • 2
  • Jeong Hyun Kwon
    • 2
  • Chan Ran Yoo
    • 2
  • Si Hyun Bae
    • 2
    Email author
  • Jong Young Choi
    • 2
  • Seung Kew Yoon
    • 2
  1. 1.Department of Internal Medicine and WHO Collaborating for Reference and Research on Viral HepatitisThe Catholic University of KoreaSeoulKorea
  2. 2.Division of Hepatology, Department of Internal Medicine, College of MedicineThe Catholic University of KoreaSeoulKorea

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