Ih. Hall et Sd. Wyrick, THE CYTOTOXICITY OF LKYL-1,3-DIOXO-1H,3H-ISOINDOLIN-5-YL)OXY]-ALKANOIC ACIDS IN MURINE AND HUMAN TISSUE-CULTURED CELL-LINES, Anticancer research, 15(4), 1995, pp. 1365-1369
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.