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.

Statistics

0204060'02'04'06'08'10'12'14'16
Citations per Year

66 Citations

Semantic Scholar estimates that this publication has 66 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Cummings1996CharacterizationOT, title={Characterization of the major metabolite of the novel topoisomerase I inhibitor NU/ICRF 505.}, author={Jeffrey D. Cummings and Ian Meikle and Janet S. Macpherson and J F Smyth}, journal={Anti-cancer drug design}, year={1996}, volume={11 5}, pages={367-82} }