title: 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.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: P-T
authors.initials: PT
authors.lastname: Huang
authors.forename: K-C
authors.initials: KC
authors.lastname: Chen
authors.forename: Z M
authors.initials: ZM
authors.lastname: Prijovich
authors.forename: T-L
authors.initials: TL
authors.lastname: Cheng
authors.forename: Y-L
authors.initials: YL
authors.lastname: Leu
authors.forename: S R
authors.initials: SR
authors.lastname: Roffler
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D024201:Bystander Effect; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005965:Glucuronates / Q000633:toxicity; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D011355:Prodrugs; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin