The effect of cyclic nucleotides on DNA polymerase, thymidylate synthetase, thymidine kinase and deoxynucleoside levels of Waler carcinoma.

Monobutyryl adenosine 3',5' monophosphate (mbcAMP) caused an inhibition of the thymidylate synthetase activity of Walker rat mammary carcinoma cells in tissue culture, which could be reversed by concomitant treatment with N2,O2' dibutyryl guanosine 3',5' monophosphate (dbcGMP). There was no effect on thymidine kinase activity. The DNA polymerase activity of whole cells, but not broken-cell preparations was markedly inhibited by a dose of mbcAMP (100 micrograms/ml) having little effect on growth rate. This inhibition could be reversed to some extent by simultaneous treatment of the cells with caffeine. Treatment with mbcAMP produced a decrease in the level of dTTP and a concomitant rise in the levels of dATP, dGTP and dCTP. This situation was reversed in combination with dbcGMP, with levels of the deoxyribonucleoside triphosphates tending to revert back to control values. The effect of mbcAMP on thymidylate synthetase and DNA polymerase may account for its growth inhibitory effect.