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Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

Abstract

We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1–5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

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References

  • Alderson RF, Birse CE, Bloom M, Connolly K, Choi GH, Fox NL et al. (2003). 94th AACR Annual Meeting, Abstract 963.

  • Almasan A, Ashkenazi A . (2003). Cytokine Growth Factor Rev 14: 337–348.

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. (1999). J Clin Invest 104: 155–162.

  • Attard G, Plummer R, de Bono JS, Bale C, Pacey S, Barrett M et al. (2005). AACR-NCI-EORTC International Conference on Molecular Therapeutics. Abstract B114.

  • Belka C, Gruber C, Jendrossek V, Wesselborg S, Budach W . (2003). Oncogene 22: 176–185.

  • Belka C, Jendrossek V, Pruschy M, Vink S, Verheij M, Budach W . (2004). Int J Radiat Oncol Biol Phys 58: 542–554.

  • Belka C, Schmid B, Marini P, Durand E, Rudner J, Faltin H et al. (2001). Oncogene 20: 2190–2196.

  • Broaddus VC, Dansen TB, Abayasiriwardana KS, Wilson SM, Finch AJ, Swigart LB et al. (2005). J Biol Chem 280: 12486–12493.

  • Buchsbaum DJ, Zhou T, Grizzle WE, Oliver PG, Hammond CJ, Zhang S et al. (2003). Clin Cancer Res 9: 3731–3741.

  • Cecconi F . (1999). Cell Death Differ 6: 1087–1098.

  • Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . (1997). Immunity 7: 821–830.

  • Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL et al. (2000). Proc Natl Acad Sci USA 97: 1754–1759.

  • Chuntharapai A, Dodge K, Grimmer K, Schroeder K, Marsters SA, Koeppen H et al. (2001). J Immunol 166: 4891–4898.

  • Daniel PT, Schulze-Osthoff K, Belka C, Guner D . (2003). Essays Biochem 39: 73–88.

  • de Bono JS, Attard G, Pacey S, Greystoke A, Plummer R, Blase C et al. (2004). 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland, Abstract 197.

  • Debatin KM, Poncet D, Kroemer G . (2002). Oncogene 21: 8786–8803.

  • El-Zawahry A, McKillop J, Voelkel-Johnson C . (2005). BMC Cancer 5: 2.

  • Fischer U, Janicke RU, Schulze-Osthoff K . (2003). Cell Death Differ 10: 76–100.

  • Fulda S, Wick W, Weller M, Debatin KM . (2002). Nat Med 8: 808–815.

  • Griffith TS, Rauch CT, Smolak PJ, Waugh JY, Boiani N, Lynch DH et al. (1999). J Immunol 162: 2597–2605.

  • Hamasu T, Inanami O, Asanuma T, Kuwabara M . (2005). J Radiat Res 46: 103–110.

  • Harris AL . (2002). Nat Rev Cancer 2: 38–47.

  • Hotte SJ, Oza AM, Le LH, MacLean M, Iacobucci A, Corey A et al. (2004). 94th AACR Annual Meeting, Geneva, Switzerland, Abstract.

  • Jendrossek V, Muller I, Eibl H, Belka C . (2003). Oncogene 22: 2621–2631.

  • Kaplan EL, Meier E . (1958). J Am Stat Assoc 53: 457–481.

  • Kim MR, Lee JY, Park MT, Chun YJ, Jang YJ, Kang CM et al. (2001). FEBS Lett 505: 179–184.

  • LeBlanc HN, Ashkenazi A . (2003). Cell Death Differ 10: 66–75.

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al. (1997). Cell 91: 479–489.

  • Luciano F, Ricci JE, Herrant M, Bertolotto C, Mari B, Cousin JL et al. (2002). Leukemia 16: 700–707.

  • Marini P, Belka C . (2003). Curr Med Chem Anti-Cancer Agents 3: 334–342.

  • Marini P, Jendrossek V, Durand E, Gruber C, Budach W, Belka C . (2003). Radiother Oncol 68: 189–198.

  • Marini P, Schmid A, Jendrossek V, Faltin H, Daniel PT, Budach W et al. (2005). BMC Cancer 5: 5.

  • Miyashita T, Reed JC . (1995). Cell 80: 293–299.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J et al. (1996). Cell 85: 817–827.

  • Nakano K, Vousden KH . (2001). Mol Cell 7: 683–694.

  • Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ . (2001). J Cell Biol 153: 1265–1276.

  • Norbury CJ, Zhivotovsky B . (2004). Oncogene 23: 2797–2808.

  • Pukac P, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C et al. (2005). Br J Cancer 92: 1430–1441.

  • Rohn TA, Wagenknecht B, Roth W, Naumann U, Gulbins E, Krammer PH et al. (2001). Oncogene 20: 4128–4137.

  • Rudner J, Jendrossek V, Lauber K, Daniel PT, Wesselborg S, Belka C . (2005). Oncogene 24: 130–140.

  • Rubel A, Handrick R, Lindner LH, Steiger M, Eibl H, Budach W et al. (2006). Radiat Oncol 1:6.

  • Salcedo TW, Alderson RF, Basu S, Beatty S, Choi GH, Corcoran M et al. (2002). American Association for Cancer Research 93rd Annual Meeting. Abstract 4240.

  • Sarantopoulos J, Wakelee H, Mita M, Fitzgerald AM, Hill M, Fox NL et al. (2005). AACR-NCI-EORTC International Conference on Molecular Therapeutics, Abstract.

  • Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T et al. (1997). Immunity 7: 831–836.

  • Shankar S, Singh TR, Chen X, Thakkar H, Firnin J, Srivastava RK . (2004a). Int J Oncol 24: 1133–1140.

  • Shankar S, Singh TR, Srivastava RK . (2004b). Prostate 61: 35–49.

  • Stroh C, Schulze-Osthoff K . (1998). Cell Death Differ 5: 997–1000.

  • Stüben G, Budach W, Schick KH, Stuschke M, Stapper N, Müller S et al. (1994). Strahlenther Onkol 170: 36–41.

  • Stuschke M, Budach V, Bamberg M, Budach W . (1990). Radiat Res 122: 172–180.

  • Tolcher AW, Mita M, Patnaik A, Rowinsky EK, Corey A, Fleming H et al. (2004). American Society of Clinical Oncology Annual Meeting, Abstract 3060.

  • von Haefen C, Gillissen B, Hemmati PG, Wendt J, Guner D, Mrozek A et al. (2004). Oncogene 23: 8320–8332.

  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. (1999). Nat Med 5: 157–163.

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. (2001). Science 292: 727–730.

  • Weinmann M, Jendrossek V, Guner D, Goecke B, Belka C . (2004a). FASEB J 18: 1906–1908.

  • Weinmann M, Marini P, Jendrossek V, Betsch A, Goecke B, Budach W et al. (2004b). Int J Radiat Oncol Biol Phys 58: 386–396.

  • Wendt J, von Haefen C, Hemmati P, Belka C, Dorken B, Daniel PT . (2005). Oncogene 24: 4052–4064.

  • Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B . (2000). Science 290: 989–992.

  • Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB . (2001). Genes Dev 15: 1481–1486.

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Acknowledgements

We thank Bert Vogelstein for kindly providing HCT 116 (Bax−/− and wild-type) cells and Katrin Stasch for technical assistance. We also wish to thank Stefanie Halene cordially for editing the English manuscript. This work was supported by a grant from the Federal Ministry of Education and Research (Fö: 1456-00) to CB and VJ and continuously by the ‘Deutsche Krebshilfe’ (Grants 10-1764 Be1 and 10-2220 Be4) to CB, PM and WB. This work is dedicated to the 75th birthday of Professor Dr Günter Brittinger.

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Marini, P., Denzinger, S., Schiller, D. et al. Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo. Oncogene 25, 5145–5154 (2006). https://doi.org/10.1038/sj.onc.1209516

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