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

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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.

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Abbreviations

HCC:

Hepatocellular carcinoma

MTD:

Maximum tolerated dose

MET:

Metronomic

VEGF:

Vascular endothelial growth factor

DEN:

Diethylnitrosamine

CTX:

Cyclophosphamide

PCNA:

Proliferating cell nuclear antigen

vWF:

von-Willebrand factor

RT-PCR:

Reverse transcription-polymerase chain reaction

PAGE:

Polyacylamide gel electrophoresis

References

  1. Block TM, Mehta AS, Fimmel CJ, Jordan R (2003) Molecular viral oncology of hepatocellular carcinoma. Oncogene 22:5093–5107

    Article  CAS  PubMed  Google Scholar 

  2. Song TJ, Ip EW, Fong Y (2004) Hepatocellular carcinoma: current surgical management. Gastroenterology 127:248–260

    Article  Google Scholar 

  3. Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922

    Article  CAS  PubMed  Google Scholar 

  4. Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047

    Article  CAS  PubMed  Google Scholar 

  5. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  CAS  PubMed  Google Scholar 

  6. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    CAS  PubMed  Google Scholar 

  7. Gasparini G (2001) Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2:733–740

    Article  CAS  PubMed  Google Scholar 

  8. Stempak D, Seely D, Baruchel S (2006) Metronomic dosing of chemotherapy: applications in pediatric oncology. Cancer Invest 24:432–443

    Article  CAS  PubMed  Google Scholar 

  9. Giavazzi R, Taraboletti G (1999) Angiogenesis and angiogenesis inhibitors in cancer. Forum (Genova) 9:261–272

    CAS  Google Scholar 

  10. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    Article  CAS  PubMed  Google Scholar 

  11. Veikkola T, Alitalo K (1999) VEGFs, receptors and angiogenesis. Semin Cancer Biol 9:211–220

    Article  CAS  PubMed  Google Scholar 

  12. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  CAS  PubMed  Google Scholar 

  13. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  CAS  PubMed  Google Scholar 

  14. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    Article  CAS  PubMed  Google Scholar 

  15. Ferrara N, Gerber HP, Le Couter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  16. Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342–4346

    CAS  PubMed  Google Scholar 

  17. Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731–2735

    CAS  PubMed  Google Scholar 

  18. Stolting S, Klink T, Bela C, Engels C, Wagner T (2004) Metronomic scheduling of trofosfamide chemotherapy in human NSCLC xenografts highly increases therapeutic efficacy compared to conventional scheduling by inhibition of angiogenesis. Int J Clin Pharmacol Ther 42:652–653

    CAS  PubMed  Google Scholar 

  19. Lee TY, Kim KT, Han SY (2007) Expression of ErbB receptor proteins and TGF-alpha during diethylnitrosamine-induced hepatocarcinogenesis in the rat liver. Korean J Hepatol 13:70–80

    PubMed  Google Scholar 

  20. Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, Clergue F, Poupon R, Barbu V, Rosmorduc O (2005) Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41:307–314

    Article  CAS  PubMed  Google Scholar 

  21. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    Article  CAS  PubMed  Google Scholar 

  22. Pang LP, Huang W, Sun Q, Guo W, Li RT, Cui JR (2008) SLXM-2, a derivative of cyclophosphamide: mechanism of growth inhibition on hepatocarcinoma 22 cells. Anticancer Drugs 19:167–174

    Article  CAS  PubMed  Google Scholar 

  23. Lindner G, Botchkarev VA, Botchkareva NV, Ling G, van der Veen C, Paus R (1997) Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol 151:1601–1617

    CAS  PubMed  Google Scholar 

  24. Mirkes PE, Little SA (2000) Cytochrome c release from mitochondria of early postimplantation murine embryos exposed to 4-hydroperoxycyclophosphamide, heat shock, and staurosporine. Toxicol Appl Pharmacol 162:197–206

    Article  CAS  PubMed  Google Scholar 

  25. Shaked Y, Emmenegger U, Francia G, Chen L, Lee CR, Man S, Paraghamian A, Ben-David Y, Kerbel RS (2005) Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res 65:7045–7051

    Article  CAS  PubMed  Google Scholar 

  26. Miller KD, Sweeney CJ, Sledge GW Jr (2001) Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19:1195–1206

    CAS  PubMed  Google Scholar 

  27. Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M, Lanz C, Buttner M, Rziha HJ, Dehio C (1999) A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 18:363–374

    Article  CAS  PubMed  Google Scholar 

  28. Rahimi N, Dayanir V, Lashkari K (2000) Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem 275:16986–16992

    Article  CAS  PubMed  Google Scholar 

  29. Veikkola T, Alitalo K (1999) VEGFs, receptors and angiogenesis. Semin Cancer Biol 9:211–220

    Article  CAS  PubMed  Google Scholar 

  30. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205:275–292

    Article  CAS  PubMed  Google Scholar 

  31. Raguz S, Yague E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99:387–391

    Article  CAS  PubMed  Google Scholar 

  32. Jia LJ, Wei DP, Sun QM, Jin GH, Li SF, Huang Y, Hua ZC (2007) Tumor-targeting Salmonella typhimurium improves cyclophosphamide chemotherapy at maximum tolerated dose and low-dose metronomic regimens in a murine melanoma model. Int J Cancer 121:666–674

    Article  CAS  PubMed  Google Scholar 

  33. Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V (2003) Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 63:8408–8413

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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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Authors and Affiliations

  1. Department of Internal Medicine and WHO Collaborating for Reference and Research on Viral Hepatitis, The Catholic University of Korea, Seoul, Korea

    Seong Tae Park, Gi Dae Kim, Joung Ah Park & Wonhee Hur

  2. Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #505 Banpodong, Seochogu, Seoul, 137-040, Korea

    Jeong Won Jang, Hyun Young Woo, Jin Dong Kim, Jeong Hyun Kwon, Chan Ran Yoo, Si Hyun Bae, Jong Young Choi & Seung Kew Yoon

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  1. Seong Tae Park
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Correspondence to Si Hyun Bae.

Additional information

S. T. Park and J. W. Jang equally contributed to this work.

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Park, S.T., Jang, J.W., Kim, G.D. et al. Beneficial effect of metronomic chemotherapy on tumor suppression and survival in a rat model of hepatocellular carcinoma with liver cirrhosis. Cancer Chemother Pharmacol 65, 1029–1037 (2010). https://doi.org/10.1007/s00280-009-1108-4

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  • DOI: https://doi.org/10.1007/s00280-009-1108-4

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