Development of anthracenyl-amino acid conjugates as topoisomerase I and II inhibitors that circumvent drug resistance.
Anthracenyl-amino acid conjugates (AAC) represent a novel class of topoisomerase (topo) inhibitor. The relationship between mechanism of enzyme inhibition and in vitro cytotoxicity has been investigated in a panel of 5 Chinese hamster ovary (CHO) and 2 human ovarian cancer cell lines (A2780) shown to possess different drug resistance phenotypes associated with altered expression of topo I and topo II. From a total of 13 compounds, 4 displayed broad-spectrum activity (IC50 ranging from 3.5-29.7 microM). NU/ICRF 500 (topo II catalytic inhibitor) was 1.4-fold more active against CHO ADR-1, which overexpresses topo II and was essentially noncross-resistant in CHO ADR-r (13.9-fold resistant to doxorubicin (DOX)) and 2780AD (1,460-fold resistant to DOX). NU/ICRF 505, which stabilises topo I cleavable complexes, was noncross-resistant in CHO ADR-3 (3,4-fold resistant to camptothecin) and only 1.8-fold cross-resistant in 2780AD. Hypersensitivity was recorded in ADR-r that overexpresses topo I. The most active compound was NU/ICRF 506, a dual catalytic inhibitor of topo I and II. Hypersensitivity was observed in ADR-r (1.4-fold) but not ADR-1, indicating that topo I is the likely nuclear target, and a low level of resistance was seen in the CHO ADR-6 drug transport mutant and 2780AD. The topo II catalytic inhibitor NU/ICRF 513 only produced hypersensitivity in ADR-r. These data suggest that NU/ICRF 500, 505, and 506 induce cell death, at least partly, through topo inhibition. NU/ICRF 513 appears to be cytotoxic via a nontopo mechanism of action. In addition, NU/ICRF 505 significantly inhibited the growth of two human xenografts (HT-29 colon cancer and NX002 nonsmall-cell lung cancer) in nude mice after i.p. administration at a dose of 25 mg/kg. The important properties of noncross-resistance and in vivo antitumour activity merit further development of AAC as potential new anticancer drugs.
Cummings
J
J
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Macpherson
J S
JS
Meikle
I
I
Smyth
J F
JF
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D004264:DNA Topoisomerases, Type I / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000596:Amino Acids; D004791:Enzyme Inhibitors; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I