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: J Cummings, I Meikle, J S Macpherson, J F Smyth
• Journal: Anti-cancer drug design (Anticancer Drug Des) Vol. 11 Issue 5 Pg. 367-82 (Jul 1996) ISSN: 0266-9536 [Print] United States
• PMID: 8765530 (Publication Type: Journal Article)

Chemical References

• Anthraquinones
• Antineoplastic Agents
• Enzyme Inhibitors
• NU-ICRF 505
• Topoisomerase I Inhibitors
• Tyrosine

Topics

• Animals
• Anthraquinones (metabolism, pharmacology, therapeutic use)
• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Biotransformation
• Carcinoma, Non-Small-Cell Lung
• Cell Division (drug effects)
• Cell Line
• Chromatography, High Pressure Liquid
• Colonic Neoplasms (drug therapy)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (metabolism, pharmacology, therapeutic use)
• Female
• Humans
• Liver (metabolism)
• Lung Neoplasms
• Mice
• Mice, Nude
• Molecular Structure
• Ovarian Neoplasms
• Spectrometry, Mass, Fast Atom Bombardment
• Topoisomerase I Inhibitors
• Transplantation, Heterologous
• Tyrosine (analogs & derivatives, metabolism, pharmacology, therapeutic use)