THE CYTOTOXICITY OF LKYL-1,3-DIOXO-1H,3H-ISOINDOLIN-5-YL)OXY]-ALKANOIC ACIDS IN MURINE AND HUMAN TISSUE-CULTURED CELL-LINES

Substituted isoindoline-1,3-diones are effective cytotoxic agents, cau sing cell death in a number of tissue culture lines, e.g. L1210, Tmolt -3, and HeLa-S-3. In general these agents were not active against the solid cell growth, i.e. KB, skin, colon HCT-8 ileum, colon, bronchogen ic lung, osteosarcoma and glioma. The mode of action of the derivative s involves inhibition of de novo purine synthesis of Tmolt-3 cells, wh ich reduces DNA and RNA syntheses. Purine synthesis was I educed by co mpound 4 at both regulatory enzymes, i.e. PRPP amido transferase and I MP dehydrogenase. The agent lowered d(GTP) pools, fur ther reducing DN A synthesis. DNA strand scission was evident after incubation with Com pound 4 for 24 hr at 100 mu M, lowering DNA synthesis and causing cell death.