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Investigation of the efficacy of a bevacizumab-cetuximab-cisplatin regimen in treating head and neck squamous cell carcinoma in mice

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Abstract

The efficacy of bevacizumab plus cetuximab-based chemotherapy remains unclear in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the anticancer efficacy of a bevacizumab-cetuximab-cisplatin triple-agent combination in treating mouse HNSCC. SCC-VII tumor-bearing C3H mice were treated with bevacizumab, cetuximab and cisplatin either alone or in various combinations. In vivo results showed that the largest delay in tumor growth and the maximum increase in survival were not in the triple-agent combination therapy, but in the bevacizumab plus cisplatin therapy. TUNEL assay showed that the apoptosis indices in bevacizumab plus cisplatin group and a triple-agent combination group were 31.6 ± 12.0% and 6.9 ± 1.3%, respectively. Western blot showed that down-regulation of Bcl-2 and up-regulation of cleaved caspase-3 contributed to the anticancer effect of a triple-agent combination and bevacizumab plus cisplatin. Moreover, the maximum level of cleaved caspase-3 expression was not found in the triple-agent combination group but in the bevacizumab plus cisplatin group. Bevacizumab plus cisplatin therapy is better than bevacizumab-cetuximab-cisplatin triple therapy in the mouse HNSCC model. Our findings suggest that the bevacizumab-cetuximab-cisplatin regimen may not be suitable for treating HNSCC.

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References

  1. Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5(3):203–220

    Article  CAS  PubMed  Google Scholar 

  2. Imai K, Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6(9):714–727

    Article  CAS  PubMed  Google Scholar 

  3. Marshall J (2006) Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 107(6):1207–1218

    Article  CAS  PubMed  Google Scholar 

  4. No authors listed (2004) Two new drugs for colon cancer. Med Lett Drugs Ther 46(1184):46–48

    Google Scholar 

  5. Aita M, Fasola G, Defferrari C, Brianti A, Bello MG, Follador A, Sinaccio G, Pronzato P, Grossi F (2008) Targeting the VEGF pathway: Antiangiogenic strategies in the treatment of non-small cell lung cancer. Crit Rev Oncol Hematol 68(3):183–196

    Article  PubMed  Google Scholar 

  6. American Cancer Society (2008) Cancer facts & figures 2008. Atlanta: American Cancer Society 2008:15–16

    Google Scholar 

  7. Tejani MA, Cohen RB, Mehra R (2010) The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics 4:173–185

    CAS  PubMed  Google Scholar 

  8. Fujita K, Sano D, Kimura M, Yamashita Y, Kawakami M, Ishiguro Y, Nishimura G, Matsuda H, Tsukuda M (2007) Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma. Oncol Rep 18(1):47–51

    CAS  PubMed  Google Scholar 

  9. Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A, Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE (2008) Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol 26(10):1732–1741

    Article  CAS  PubMed  Google Scholar 

  10. Merlano M, Russi E, Benasso M, Corvò R, Colantonio I, Vigna-Taglianti R, Vigo V, Bacigalupo A, Numico G, Crosetto N, Gasco M, Lo Nigro C, Vitiello R, Violante S, Garrone O (2010) Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study. Ann Oncol. doi:10.1093/annonc/mdq412

    PubMed  Google Scholar 

  11. Prichard CN, Kim S, Yazici YD, Doan DD, Jasser SA, Mandal M, Myers JN (2007) Concurrent cetuximab and bevacizumab therapy in a murine orthotopic model of anaplastic thyroid carcinoma. Laryngoscope 117(4):674–679

    Article  CAS  PubMed  Google Scholar 

  12. Bozec A, Sudaka A, Fischel JL, Brunstein MC, Etienne-Grimaldi MC, Milano G (2008) Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model. Br J Cancer 99(1):93–99

    Article  CAS  PubMed  Google Scholar 

  13. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360(6):563–572

    Article  CAS  PubMed  Google Scholar 

  14. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27(5):672–680

    Article  CAS  PubMed  Google Scholar 

  15. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F (1996) An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274(5286):373–376

    Article  CAS  PubMed  Google Scholar 

  16. Inoue K, Slaton JW, Perrotte P, Davis DW, Bruns CJ, Hicklin DJ, McConkey DJ, Sweeney P, Radinsky R, Dinney CP (2000) Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res 6(12):4874–4884

    CAS  PubMed  Google Scholar 

  17. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324(1):1–8

    Article  CAS  PubMed  Google Scholar 

  18. Tol J, Koopman M, Rodenburg CJ, Cats A, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, Mol L, Antonini NF, Punt CJ (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19(4):734–738

    Article  CAS  PubMed  Google Scholar 

  19. Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A, Vokes EE (2009) Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 10(3):247–257

    Article  CAS  PubMed  Google Scholar 

  20. Punt CJ, Tol J (2009) More is less—combining targeted therapies in metastatic colorectal cancer. Nat Rev Clin Oncol 6(12):731–733

    Article  CAS  PubMed  Google Scholar 

  21. Mandpe AH, Tsung K, Norton JA (2003) Cure of an established nonimmunogenic tumor, SCC VII, with a novel interleukin 12-based immunotherapy regimen in C3H mice. Arch Otolaryngol Head Neck Surg 129(7):786–792

    Article  PubMed  Google Scholar 

  22. O’Malley BW, Cope KA, Johnson CS, Schwartz MR (1997) A new immunocompetent murine model for oral cancer. Arch Otolaryngol Head Neck Surg 123(1):20–24

    PubMed  Google Scholar 

  23. Khurana D, Martin EA, Kasperbauer JL, O’Malley BW Jr, Salomao DR, Chen L, Strome SE (2001) Characterization of a spontaneously arising murine squamous cell carcinoma (SCC VII) as a prerequisite for head and neck cancer immunotherapy. Head Neck 23(10):899–906

    Article  CAS  PubMed  Google Scholar 

  24. Xu ZQ, Liu Y, Wang YX, Zhang W, Zhao FY (2009) Therapeutic effects of Avastin on murine hemangioendotheliaoma. Beijing Da Xue Xue Bao 41(1):105–108

    CAS  PubMed  Google Scholar 

  25. de Gramont A, Van Cutsem E (2005) Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. Oncology 69(Suppl 3):46–56

    Article  PubMed  Google Scholar 

  26. Bruns CJ, Harbison MT, Davis DW, Portera CA, Tsan R, McConkey DJ, Evans DB, Abbruzzese JL, Hicklin DJ, Radinsky R (2006) Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 6(5):1936–1948

    Google Scholar 

  27. Petros AM, Olejniczak ET, Fesik SW (2004) Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644(2–3):83–94

    CAS  PubMed  Google Scholar 

  28. Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19(5):488–496

    Article  CAS  PubMed  Google Scholar 

  29. Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B, Vallette FM (2007) Bax activation and mitochondrial insertion during apoptosis. Apoptosis 12(5):887–896

    Article  CAS  PubMed  Google Scholar 

  30. Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G (2006) Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 13(9):1423–1433

    Article  CAS  PubMed  Google Scholar 

  31. Lobo NA, Shimono Y, Qian D, Clarke MF (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675–699

    Article  CAS  PubMed  Google Scholar 

  32. Newman JR, Helman EE, Safavy S, Zhang W, Rosenthal EL (2009) EMMPRIN expression is required for response to bevacizumab therapy in HNSCC xenografts. Cancer Lett 274(2):313–318

    Article  CAS  PubMed  Google Scholar 

  33. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Nianhui Cui for providing the SCC-VII cell line for the study. This study was supported by the National Natural Science Foundation of China (39470754) and the National “985 Project” of China (985-2-040-115).

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None declared.

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Correspondence to Yixiang Wang or Shenglin Li.

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Yixiang Wang and Ling Dong contributed equally to this work.

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Wang, Y., Dong, L., Bi, Q. et al. Investigation of the efficacy of a bevacizumab-cetuximab-cisplatin regimen in treating head and neck squamous cell carcinoma in mice. Targ Oncol 5, 237–243 (2010). https://doi.org/10.1007/s11523-010-0164-3

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  • DOI: https://doi.org/10.1007/s11523-010-0164-3

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