INHIBITION OF DRUG-NAIVE AND DRUG-RESISTANT LEUKEMIA-CELL PROLIFERATION BY LOW-MOLECULAR-WEIGHT THIOLS

The aim of these studies was to investigate the ability of cysteamine and its congeners to arrest the proliferation of leukemic cells and to determine the physico-chemical properties responsible for this abilit y. Fifteen low molecular weight thiol-bearing compounds were shown to arrest the proliferation of CCRF-CEM cells and a methotrexate-resistan t subline, with IC50 values between 10(-5) and 10(-4) M. Cysteamine ar rested proliferation by slowing the passage of cells through S phase. These cells subsequently resumed cycling, although a proportion went o n to die by apoptosis. The antiproliferative action of cysteamine was shown to depend, in part, on H2O2 production. This ability to generate peroxide is shared by many thiol compounds, and molecular modeling in dicated that thiol groups were required for the antiproliferative acti ons of the congeners of cysteamine. Molecular modeling also revealed t hat the most efficacious antiproliferative agents were those that had their amino acid and thiol moieties separated by an intramolecular dis tance of 3.17 to 5.9 Angstrom, as exemplified by WR 1065 and the amino thiophenols. These findings indicate that thiol-bearing compounds may have some efficacy in the treatment of drug-naive and -resistant leuke mia cells. (C) 1998 Elsevier Science Inc.