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Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Cancer Gene Therapy volume 18, pages 381–389 (2011)Cite this article

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Abstract

CPT-11 is a clinically important prodrug that requires conversion into the active metabolite SN-38, a potent topoisomerase I poison, for antitumor activity. However, SN-38 is rapidly metabolized to the inactive SN-38 glucuronide (SN-38G) in the liver, which reduces the amount of SN-38 available for killing cancer cells. Here, we investigated if local expression of β-glucuronidase (βG) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. βG was tethered on the plasma membrane of three different human cancer cell lines: human colon carcinoma (LS174T), lung adenocarcinoma (CL1-5) and bladder carcinoma (EJ). Surface β-glucuronidase-expressing cells were 20 to 80-fold more sensitive to SN-38G than the parental cells. Intravenous CPT-11 produced significantly greater suppression of CL1-5 and LS174 T tumors that expressed βG as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered βG (Ad.βG) increased the sensitivity of cancer cells to SN-38G even at multiplicity of infections as low as 0.16, indicating bystander killing of non-transduced cancer cells. Importantly, intratumoral injection of Ad.βG significantly enhanced the in vivo antitumor activity of CPT-11 as compared with treatment with CPT-11 or Ad vectors alone. This study shows that Ad.βG has potential to boost the therapeutic index of CPT-11.

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Acknowledgements

This study was supported by grants from the Academia Sinica, Taipei, Taiwan (AS-98-TP-B09) and the National Science Council, Taipei, Taiwan (NSC-95-2311-B001-068-MY3).

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Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    P-T Huang, K-C Chen, Z M Prijovich & S R Roffler

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

    T-L Cheng

  3. Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan

    Y-L Leu

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Correspondence to S R Roffler.

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Huang, PT., Chen, KC., Prijovich, Z. et al. Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors. Cancer Gene Ther 18, 381–389 (2011). https://doi.org/10.1038/cgt.2011.3

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