DEVELOPMENT OF ANTHRACENYL-AMINO ACID CONJUGATES AS TOPOISOMERASE-I AND TOPOISOMERASE-II INHIBITORS THAT CIRCUMVENT DRUG-RESISTANCE

Anthracenyl-amino acid conjugates (AAC) represent a novel class of tup oisomerase (topo) inhibitor. The relationship between mechanism of enz yme inhibition and in vitro cytotoxicity has been investigated in a pa nel of 5 Chinese hamster ovary (CHO) and 2 human ovarian cancer cell l ines (A2780) shown to possess different drug resistance phenotypes ass ociated 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 mu M). NU/ICRF 500 (topo II catalytic inhibitor) was 1.4-fold more active against CHO ADR-1, which overexpresses topo II and was es sentially noncross-resistant in CHO ADR-r (13.9-fold resistant to doxo rubicin (DOX)) and 2780(AD) (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 cr oss-resistant in 2780(AD). Hypersensitivity was recorded in ADR-r that overexpresses topo I. The most active compound was NU/ICRF 506, a dua l 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 likel y nuclear target, and a low level of resistance was seen in the CHO AD R-6 drug transport mutant and 2780(AD). The topo II catalytic inhibito r NU/ICRF 513 only produced hypersensitivity in ADR-r. These data sugg est 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 no ntopo mechanism of action. In addition, NU/ICRF 505 significantly inhi bited 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 an d in vivo antitumour activity merit further development of AAC as pote ntial new anticancer drugs.