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Membrane-localized activation of glucuronide prodrugs by β-glucuronidase enzymes

Cancer Gene Therapy volume 14, pages 187–200 (2007)Cite this article

Abstract

Gene-mediated enzyme prodrug therapy (GDEPT) seeks to increase the therapeutic index of anti-neoplastic agents by promoting selective activation of relatively nontoxic drug derivatives at sites of specific enzyme expression. Glucuronide prodrugs are attractive for GDEPT due to their low toxicity, bystander effect in the interstitial tumor space and the large range of possible glucuronide drug targets. In this study, we expressed human, murine and Esherichia coli β-glucuronidase on tumor cells and examined their in vitro and in vivo efficacy for the activation of glucuronide prodrugs of 9-aminocamptothecin and p-hydroxy aniline mustard. We show that (1) fusion of β-glucuronidase to the Ig-like C2-type and Ig-hinge-like domains of the B7-1 antigen followed by the B7-1 transmembrane domain anchored high levels of active murine and human β-glucuronidase on cells, (2) strong bystander killing of tumor cells was achieved in vitro by murine β-glucuronidase activation of prodrug, (3) potent in vivo anti-tumor activity was achieved by prodrug treatment of tumors that expressed murine β-glucuronidase and (4) the p-hydroxy aniline prodrug was more effective in vivo than the 9-aminocamptothecin prodrug. Our results demonstrate that surface expression of murine β-glucuronidase for activation of a glucuronide prodrug of p-hydroxy aniline mustard may be useful for more selective therapy of cancer.

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Acknowledgements

Grants from the National Science Council, Taipei, Taiwan (NSC-93-2311-B-001-022) and the National Health Research Institutes (NHRI-EX94-9420B1) supported this work. We thank Andre Lieber and Daniel Stone for useful discussions.

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Authors and Affiliations

  1. Division of Cancer Research, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    K-C Chen, Z M Prijovich, B-M Chen & S R Roffler

  2. Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan

    T-L Cheng & C-H Chuang

  3. MedicoGenomic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

    T-L Cheng

  4. Department of Pharmacy, Chia-Nan College of Pharmacy and Sciences, Tainan Hsien, Taiwan

    Y-L Leu

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  1. K-C Chen
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Correspondence to S R Roffler.

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Chen, KC., Cheng, TL., Leu, YL. et al. Membrane-localized activation of glucuronide prodrugs by β-glucuronidase enzymes. Cancer Gene Ther 14, 187–200 (2007). https://doi.org/10.1038/sj.cgt.7700999

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