title: Characterization of the major metabolite of the novel topoisomerase I inhibitor NU/ICRF 505.
abstract: NU/ICRF 505 is a tyrosine conjugate of anthraquinone modified at the C terminus of the amino acid as an ethyl ester and it stabilizes topoisomerase I (topo I)-cleavable complexes. It is active in vitro against a panel of human cell lines, including drug-resistant variants, and possesses in vivo antitumour activity. NU/ICRF 505 was rapidly metabolized in nude mice to a product which represented the sole detectable form of the drug present in plasma and a chemosensitive human xenograft (HT-29 colon cancer). The metabolite (codenamed NU/ICRF 505/M) was purified, characterized by mass spectrometry and UV-visible spectroscopy, and shown to be the free amino acid produced by hydrolysis of the ethyl ester bond. NU/ICRF 505/M stabilized topo I-cleavable complexes in assays with human enzyme and was equipotent to the parent drug. Nonetheless, the metabolite was inactive in vitro against a panel of human tumour cell lines (including HT-29) and was not significantly taken up into cells in drug-uptake studies. Levels of the metabolite measured in the HT-29 xenograft after administration of a therapeutic dose of NU/ICRF 505 (25 mg/kg i.p.) remained above 1 microM for 6 h, and exceeded 10 microM at 10 min and 2 h. These data suggest that NU/ICRF 505 is a prodrug in nude mice for its topo-active metabolite NU/ICRF 505/M which accumulates in the tumour.
authors.affiliation: Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.forename: I
authors.initials: I
authors.lastname: Meikle
authors.forename: J S
authors.initials: JS
authors.lastname: Macpherson
authors.forename: J F
authors.initials: JF
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001711:Biotransformation; D002289:Carcinoma, Non-Small-Cell Lung; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010051:Ovarian Neoplasms; D016339:Spectrometry, Mass, Fast Atom Bombardment; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C100645:NU-ICRF 505; D059004:Topoisomerase I Inhibitors; D014443:Tyrosine