Journal
CANCER GENE THERAPY
Volume 18, Issue 6, Pages 381-389Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cgt.2011.3
Keywords
CPT-11; beta-glucuronidase; SN-38G; adenovirus; cancer therapy; prodrug
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Funding
- Academia Sinica, Taipei, Taiwan [AS-98-TP-B09]
- National Science Council, Taipei, Taiwan [NSC-95-2311-B001-068-MY3]
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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 beta-glucuronidase (beta G) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. beta G 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 beta-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 beta G as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered beta G (Ad.beta G) 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.beta G 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.beta G has potential to boost the therapeutic index of CPT-11. Cancer Gene Therapy (2011) 18, 381-389; doi:10.1038/cgt.2011.3; published online 25 February 2011
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