title: Anti-tumour activity and toxicity of the new prodrug 9-aminocamptothecin glucuronide (9ACG) in mice.
abstract: Cancer chemotherapy is limited by the modest therapeutic index of most antineoplastic drugs. Some glucuronide prodrugs may display selective anti-tumour activity against tumours that accumulate beta-glucuronidase. We examined the toxicity and anti-tumour activity of 9-aminocamptothecin glucuronide, a new glucuronide prodrug of 9-aminocamptothecin, to evaluate its potential clinical utility. 9-aminocamptothecin glucuronide was 25-60 times less toxic than 9-aminocamptothecin to five human cancer cell lines. Beta-glucuronidase activated 9-aminocamptothecin glucuronide to produce similar cell killing as 9-aminocamptothecin or topotecan. The in vivo toxicity of 9-aminocamptothecin glucuronide in BALB/c mice was dose-, route-, sex- and age-dependent. 9-aminocamptothecin glucuronide was significantly less toxic to female than to male mice but the difference decreased with age. 9-aminocamptothecin glucuronide and 9-aminocamptothecin produced similar inhibition (approximately 80%) of LS174T human colorectal carcinoma tumours. 9-aminocamptothecin glucuronide cured a high percentage of CL1-5 human lung cancer xenografts with efficacy that was similar to or greater than 9-aminocamptothecin, irinotecan and topotecan. The potent anti-tumour activity of 9-aminocamptothecin glucuronide suggests that this prodrug should be further evaluated for cancer treatment.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115, and ICTM, Center for Chemistry, Belgrade, Yugoslavia.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Prijovich
authors.forename: B-M
authors.initials: BM
authors.lastname: Chen
authors.forename: Y-L
authors.initials: YL
authors.lastname: Leu
authors.forename: J-W
authors.initials: JW
authors.lastname: Chern
authors.forename: S R
authors.initials: SR
authors.lastname: Roffler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004355:Drug Stability; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D012737:Sex Factors; D012995:Solubility; D019772:Topotecan / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015431:Weight Loss; D023041:Xenograft Model Antitumor Assays
chemical_list: C461385:9-aminocamptothecin glucuronide; D000970:Antineoplastic Agents; D020719:Glucuronides; D011355:Prodrugs; D019772:Topotecan; D002166:Camptothecin