title: Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation.
abstract: Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Zeljko M
authors.initials: ZM
authors.lastname: Prijovich
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.|Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica , Taipei, Taiwan.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Burnouf
authors.affiliation: Chia Nan University , Tainan 71710, Taiwan.
authors.forename: Hua-Cheng
authors.initials: HC
authors.lastname: Chou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Ping-Ting
authors.initials: PT
authors.lastname: Huang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Kai-Chuan
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University , Kaohsiung 80708, Taiwan.
authors.forename: Tian-Lu
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Chia Nan University , Tainan 71710, Taiwan.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Leu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Roffler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019772:Topotecan / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D020719:Glucuronides; D011355:Prodrugs; C080125:9-aminocamptothecin; D000077146:Irinotecan; D019772:Topotecan; D005966:Glucuronidase; D002166:Camptothecin
keywords: ADEPT; albumin influence; beta-glucuronidase; camptothecin; cancer; glucuronide; prodrug; targeted therapy