Antileukemic activity studies and cellular pharmacology of the analogues 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 the PL series, three were found to be active in cell lines sensitive (CEM/0) or resistant to ara-C (CEM/ara-C/7A; CEM/dCk[-]. The compounds PL4, 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. Combination of each of the three active PL compounds with ara-C showed high degree of synergism in comparison to the combinations of HU with ara-C against both CEM/0 and CEM/ara-C/7A cell lines. The DNA synthetic capacity of CEM/0 cells treated with 10 microM PL4 for 24 or 48 h was inhibited > or = 99.8% simultaneously the cellular NTP pools were severely depleted. Treatment of CEM/0 cells with 10 microM PL4 showed steady depletion in all the dNTP pools at 1 or 2 h and complete depletion by 4 h. The enzyme activity did not recover up to 48 h in presence of the drug suggesting irreversible inhibition of RR.
Nandy
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P
School of Pharmacy, Department of Pharmaceutical Sciences, University of Southern California, Los Angeles.
Lien
E J
EJ
Avramis
V I
VI
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D003561:Cytarabine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007211:Indoles; D003561:Cytarabine