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Combination therapy using the cyclooxygenase-2 inhibitor Parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin

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Abstract

Background: Inhibition of the COX-2 enzyme has been shown to have a radiosensitizing effect in epithelial cancers. The aim of this study was to investigate whether the efficacy of radioimmunotherapy (RIT) using 131I-labeled anti-CEA monoclonal antibody MN-14 could be enhanced by co-administration of the selective COX-2 inhibitor Parecoxib in mice with small volume (1–3 mm) peritoneal carcinomatosis of colonic origin. Methods: First, the efficacy of 14 daily injections of Parecoxib monotherapy (0 – 0.2 – 1.0 – 5.0 – 25.0 mg/kg) was determined in mice with intraperitoneal LS174T xenografts. Second, the influence of Parecoxib (1.0 or 5.0 mg/kg) on the biodistribution of 125I-MN-14 was assessed. Finally, the efficacy of RIT alone [125 μCi 131I-MN-14/mouse ≈ 1/4 of the maximal tolerated dose (MTD)] was compared with that of Parecoxib monotherapy and RIT combined with daily injections of Parecoxib (1.0 or 5.0 mg/kg). Results: Parecoxib had no measurable antitumor effect up to the highest dose level (25 mg/kg). Parecoxib had no effect on the uptake of 125I-MN-14 in the intraperitoneal tumor xenografts or on normal tissue distribution. Median survival of the control mice and the mice treated with Parecoxib monotherapy (1.0 or 5.0 mg/kg) was 48.5 days, 52 days and 52 days (P=0.47). RIT alone significantly delayed the growth of the intraperitoneal xenografts resulting in a median survival of 87 days (P<0.0001). Mice treated with RIT + Parecoxib at 1.0 or 5.0 mg/kg had a median survival of 73.5 days and 76 days, respectively, which was not statistically different from survival after RIT alone (P=0.15). Conclusion: The COX-2 inhibitor Parecoxib does not enhance the therapeutic efficacy of RIT of experimental small volume peritoneal carcinomatosis of colonic origin.

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Acknowledgments

Part of this study was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw); Grant number: 920-03-220. The authors wish to thank Mr Hennie Eikholt, animal technician, for technical assistance during the experiments, and Ms. Anneke Voss, for her help in the histopathological examination.

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Authors and Affiliations

  1. Department of Surgery, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands

    Manuel J. Koppe, Robert P. Bleichrodt & Thijs Hendriks

  2. Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Manuel J. Koppe, Wim J. G. Oyen & Otto C. Boerman

  3. Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Albert A. Verhofstad

  4. Center for Molecular Medicine and Immunology, The Garden State Cancer Center, Belleville, New Jersey, USA

    David M. Goldenberg

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  1. Manuel J. Koppe
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Correspondence to Manuel J. Koppe.

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Koppe, M.J., Oyen, W.J.G., Bleichrodt, R.P. et al. Combination therapy using the cyclooxygenase-2 inhibitor Parecoxib and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin. Cancer Immunol Immunother 55, 47–55 (2006). https://doi.org/10.1007/s00262-005-0704-3

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