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Improved Anti-tumor Activity and Safety of Interleukin-13 Receptor Targeted Cytotoxin by Systemic Continuous Administration in Head and Neck Cancer Xenograft Model

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Molecular Medicine Aims and scope

Abstract

Background

IL-13 receptor (IL-13R) targeted cytotoxin, IL13-PE38QQR, has been shown to have very potent anti-tumor activity to IL-13R-expressing head and neck tumor cells in vitro and in vivo. However, its effect is limited in aggressive tumors. To further improve the anti-tumor activity and safety of IL-13 cytotoxin, we employed continuous infusion technique in animal model of head and neck cancer.

Materials and Methods

We surgically implanted continuous infusion (CI) pump intraperitoneally that released drug for 7 days, and its anti-tumor effect was evaluated. A comparison was made for antitumor activity and safety with intravenously (IV) administered IL-13 cytotoxin in a head and neck (KCCT873 and HN12) subcutaneous (SC) xenograft tumor models in nude mice. Vital organ toxicities were assessed by histologic examinations and blood serum chemistry analyses.

Results

The 50 or 75 µg/kg/day for 7 days of IL-13 cytotoxin either by IV or CI administration did not show any difference in safety or anti-tumor activity. IV administration of 150 or 200 µg/kg/day of IL-13 cytotoxin for 7 days was lethal to nude mice, whereas 200 µg/kg/day X 7 days of CI administration was highly effective in the regression of established tumors without any toxicities. Additionally, CI administration of IL-13 cytotoxin (200 µg/kg/day) showed growth inhibition of larger HN12 tumors in nude mice.

Conclusion

With a CI schedule, IL-13 cytotoxin can be systemically administrated at approximately twice the dose otherwise given by daily IV bolus administration.

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Acknowledgments

We thank Ms. Pamela Dover for the procurement of reagents and technical assistance, and Dr Bharat H. Joshi for providing recombinant IL13-PE38QQR. We also thank Drs Raymond P. Donnelly and David Essayan of CBER/FDA for reading this manuscript. These studies were conducted as part of a collaboration between the FDA and NeoPharm Inc. under a Cooperative Research and Development Agreement (CRADA).

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Authors and Affiliations

  1. Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Building 29B, Room 2NN10, 29 Lincoln Drive MSC 4555, Bethesda, MD, 20892, USA

    Koji Kawakami, Syed R. Husain, Mariko Kawakami & Raj K. Puri

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  1. Koji Kawakami
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  2. Syed R. Husain
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  3. Mariko Kawakami
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Correspondence to Raj K. Puri.

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Kawakami, K., Husain, S.R., Kawakami, M. et al. Improved Anti-tumor Activity and Safety of Interleukin-13 Receptor Targeted Cytotoxin by Systemic Continuous Administration in Head and Neck Cancer Xenograft Model. Mol Med 8, 487–494 (2002). https://doi.org/10.1007/BF03402028

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