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

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.

• Authors: P-T Huang, K-C Chen, Z M Prijovich, T-L Cheng, Y-L Leu, S R Roffler
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 18 Issue 6 Pg. 381-9 (Jun 2011) ISSN: 1476-5500 [Electronic] England
• PMID: 21350582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-ethyl-10-hydroxycamptothecin beta-glucuronide
• Antineoplastic Agents, Phytogenic
• Glucuronates
• Prodrugs
• Irinotecan
• Glucuronidase
• Camptothecin

Topics

• Adenoviridae (genetics)
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Bystander Effect
• Camptothecin (analogs & derivatives, therapeutic use, toxicity)
• Combined Modality Therapy
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Glucuronates (toxicity)
• Glucuronidase (genetics, metabolism)
• Humans
• Irinotecan
• Neoplasms (drug therapy, therapy)
• Prodrugs (therapeutic use)
• Tumor Cells, Cultured