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Effective antitumour mono- and combination therapy by gene delivery of angiostatin-like molecule and interleukin-12 in a murine hepatoma model

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Methods

We applied an experimental approach employing two recombinant adenoviral vectors (Ad) that express interleukin-12 (IL-12) and angiostatin-like molecule (K1-3) respectively to a subcutaneous hepatoma model in mice.

Results

Injection of AdK1-3 into tumour nodules established by subcutaneous (s.c.) implantation of Hepa129 hepatoma cells in C3H mice resulted in a significant dose-dependent reduction in tumour growth by 57% in the high dosage group (5×109 plaque-forming units [pfu], n=8) 10 days after treatment initiation. Similar antitumoural effects were found for the intratumoural mono-therapy with IL-12 (2.5×109 pfu, n=8) resulting in 60% tumour inhibition at the same time point. The survival rate was significantly (p=0.009) improved in the IL-12 but not in the K1-3 treatment group. A combination therapy of AdK1-3 and AdIL-12 was also effective, but did not further improve antitumour efficacy compared with the monotherapy.

Conclusion

In conclusion, both mono- and combination therapy of K1-3 and IL-12 significantly inhibited tumour progression in this experimental tumour model. The co-administration of both compounds did not result in additive antitumour effects. We hypothesise that the lack of additive antitumour effects of the combination treatment might be attributed to partially counteracting antitumour effects and further studies are needed to illustrate the interference of tumour angiogenesis and tumour inflammation in this tumour model.

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References

  1. Lau WY (2000) Primary liver tumors. Semin Surg Oncol 19:135–144

    Article  CAS  PubMed  Google Scholar 

  2. Lau WY, Leung TW, Yu SC, Ho SK (2003) Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Ann Surg 237:171–179

    Article  CAS  PubMed  Google Scholar 

  3. Yu AS, Keeffe EB (2003) Management of hepatocellular carcinoma. Rev Gastroenterol Disord 3:8–24

    CAS  PubMed  Google Scholar 

  4. Okuda K (2000) Hepatocellular carcinoma. J Hepatol 32:225–237

    Article  CAS  PubMed  Google Scholar 

  5. Mazzolini G, Prieto J, Melero I (2003) Gene therapy of cancer with interleukin-12. Curr Pharm Des 9:1981–1991

    Article  CAS  PubMed  Google Scholar 

  6. Prieto J, Herraiz M, Sangro B, Qian C, Mazzolini G, Melero I et al (2003) The promise of gene therapy in gastrointestinal and liver diseases. Gut 52 [Suppl 2]:ii49–ii54

    Article  CAS  PubMed  Google Scholar 

  7. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  CAS  PubMed  Google Scholar 

  8. Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J (1995) Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87:581–586

    CAS  PubMed  Google Scholar 

  9. Barajas M, Mazzolini G, Genove G, Bilbao R, Narvaiza I, Schmitz V et al (2001) Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology 33:52–61

    Article  CAS  PubMed  Google Scholar 

  10. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Cao Y et al (1994) Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 59:471–482

    CAS  PubMed  Google Scholar 

  11. Ishikawa H, Nakao K, Matsumoto K, Ichikawa T, Hamasaki K, Nakata K et al (2003) Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene. Hepatology 37:696–704

    Article  CAS  PubMed  Google Scholar 

  12. Schmitz V, Wang L, Barajas M, Gomar C, Prieto J, Qian C (2004) Treatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene transfer of endostatin and angiostatin-like molecule in mice. Gut 53:561–567

    Article  CAS  PubMed  Google Scholar 

  13. Schmitz V, Wang L, Barajas M, Peng D, Prieto J, Qian C (2002) A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen. Gene Ther 9:1600–1606

    Article  CAS  PubMed  Google Scholar 

  14. Gyorffy S, Palmer K, Podor TJ, Hitt M, Gauldie J (2001) Combined treatment of a murine breast cancer model with type 5 adenovirus vectors expressing murine angiostatin and IL-12: a role for combined anti-angiogenesis and immunotherapy. J Immunol 166:6212–6217

    CAS  PubMed  Google Scholar 

  15. Wilczynska U, Kucharska A, Szary J, Szala S (2001) Combined delivery of an antiangiogenic protein (angiostatin) and an immunomodulatory gene (interleukin-12) in the treatment of murine cancer. Acta Biochim Pol 48:1077–1084

    CAS  PubMed  Google Scholar 

  16. Mazzolini G, Qian C, Xie X, Sun Y, Lasarte JJ, Drozdzik M et al (1999) Regression of colon cancer and induction of antitumor immunity by intratumoral injection of adenovirus expressing interleukin-12. Cancer Gene Ther 6:514–522

    Article  CAS  PubMed  Google Scholar 

  17. Coussens LM, Werb Z (2001) Inflammatory cells and cancer: think different! J Exp Med 193:F23–F26

    Article  CAS  PubMed  Google Scholar 

  18. Qin LX, Tang ZY (2002) The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 8:385–392

    CAS  PubMed  Google Scholar 

  19. Park YN, Kim YB, Yang KM, Park C (2000) Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 124:1061–1065

    CAS  PubMed  Google Scholar 

  20. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L (2003) VEGF-receptor signal transduction. Trends Biochem Sci 28:488–494

    Article  CAS  PubMed  Google Scholar 

  21. Zachary I (2003) Vascular endothelial growth factor and anti-angiogenic peptides as therapeutic and investigational molecules. IDrugs 6:224–231

    CAS  PubMed  Google Scholar 

  22. Masson VV, Devy L, Grignet-Debrus C, Bernt S, Bajou K, Blacher S et al (2002) Mouse aortic ring assay: a new approach of the molecular genetics of angiogenesis. Biol Proced Online 4:24–31

    Article  CAS  PubMed  Google Scholar 

  23. Yao L, Sgadari C, Furuke K, Bloom ET, Teruya-Feldstein J, Tosato G (1999) Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood 93:1612–1621

    CAS  PubMed  Google Scholar 

  24. Yao L, Pike SE, Setsuda J, Parekh J, Gupta G, Raffeld M et al (2000) Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood 96:1900–1905

    CAS  PubMed  Google Scholar 

  25. Narvaiza I, Mazzolini G, Barajas M, Duarte M, Zaratiegui M, Qian C et al (2000) Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible protein-10 and another encoding IL-12, results in marked antitumoral synergy. J Immunol 164:3112–3122

    CAS  PubMed  Google Scholar 

  26. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  Google Scholar 

  27. Benelli R, Morini M, Carrozzino F, Ferrari N, Minghelli S, Santi L et al (2002) Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J 16:267–269

    CAS  PubMed  Google Scholar 

  28. Ramanathan M, Giladi A, Leibovich SJ (2003) Regulation of vascular endothelial growth factor gene expression in murine macrophages by nitric oxide and hypoxia. Exp Biol Med (Maywood) 228:697–705

    CAS  Google Scholar 

  29. Iijima K, Yoshikawa N, Nakamura H (1996) Activation-induced expression of vascular permeability factor by human peripheral T cells: a non-radioisotopic semiquantitative reverse transcription-polymerase chain reaction assay. J Immunol Methods 196:199–209

    Article  CAS  PubMed  Google Scholar 

  30. Mendoza L, Valcarcel M, Carrascal T, Egilegor E, Salado C, Sim BK et al (2004) Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis. Cancer Res 64:304–310

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partly supported by a BONFOR and Deutsche Krebshilfe grant to V.S. and N.W.

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Author notes

  1. Wolfgang H. Caselmann

    Present address: Bavarian State Ministry of the Environment, Public Health and Consumer Protection, Munich, Germany

Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany

    Volker Schmitz, Lucia Tirado-Ledo, Esther Raskopf, Christian Rabe, Tilman Sauerbruch & Wolfgang H. Caselmann

  2. Institute of Pathology, University Hospital Bonn, Bonn, Germany

    Nicolas Wernert

  3. Gene Therapy Unit, University of Navarra, Clínica Universitaria and Medical School, Pamplona, Spain

    Lin Wang, Jesús Prieto & Cheng Qian

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  1. Volker Schmitz
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  2. Lucia Tirado-Ledo
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Correspondence to Volker Schmitz.

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Schmitz, V., Tirado-Ledo, L., Raskopf, E. et al. Effective antitumour mono- and combination therapy by gene delivery of angiostatin-like molecule and interleukin-12 in a murine hepatoma model. Int J Colorectal Dis 20, 494–501 (2005). https://doi.org/10.1007/s00384-004-0727-9

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  • DOI: https://doi.org/10.1007/s00384-004-0727-9

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