ANTILEUKEMIC ACTIVITY STUDIES AND CELLULAR PHARMACOLOGY OF THE ANALOGS OF 2-HYDROXY-1H-ISOINDOLE-1,3-DIONE (HISD) ALONE AND IN COMBINATION WITH CYTOSINE-ARABINOSIDE (ARA-C) AGAINST HUMAN LEUKEMIA-CELLS CEM 0/

The 2-hydroxy-1H-isoindole-1,3-dione (HISD) derivatives are inhibitors of ribonucleotide reductase (RR). Among the seven new compounds of th e PL series, three were found to be active in cell lines sensitive (CE M/0) or resistant to ara-C (CEM/ara-C/7A; CEM/dCk[-]). The compounds P L4, PL7 and PL8 exhibited IC50 values in micromolar range against the three CEM cell lines. The 3 compounds showed 100- to 1000-fold higher cytotoxicity compared to HU against all three CEM cell lines. Combinat ion of each of the three active PL compounds with ara-C showed high de gree of synergism in comparison to the combinations of HU with ara-C a gainst both CEM/0 and CEM/ara-C/7A cell lines. The DNA synthetic capac ity of CEM/0 cells treated with 10 mu M PL4 for 24 or 48 h was inhibit ed 3 99.8% simultaneously the cellular NTP pools were severely deplete d. Treatment of CEM/0 cells with 10 mu M PL4 showed steady depletion i n all the dNTP pools at 1 or 2 h and complete depletion by 4 h. The en zyme activity did not recover up to 48 h in presence of the drug sugge sting irreversible inhibition of RR.