Synthesis and biochemical evaluation of 6-methylthioinosine-3'', 5''-cyclic monophosphate in L1210 and Ehrlich ascites cells



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Methylthioinosine-3'.5'-monophosphate (c-MTIMP) was synthesized for use in circumventing tumor resistance to methylthioinosine (MTI). c-MTIMP was hydrolyzed to MTIMP by both bovine cyclic phosphodiesterase and extracts of L1210 cells, and showed potent feedback inhibition of de novo purine biosynthesis in Ehrlich and L1210 cells resistant to MTI as well as on both sensitive cell lines. The data showed that c-MTIMP entered the cell membrane and was hydrolyzed to MTIMP which inhibited the phosphorylpyrophosphate amidotransferase in both the L1210 and the Ehrlich ascites cells. Also MTI was found to inhibit the PRPP amidotransferase of L1210 cells resistant to MTI whereas the enzyme of Ehrlich cells resistant to MTI was not sensitive to MTI. Adenosine also gave feedback inhibition in the MTI resistant cell lines. Neither MTI or c-MTIMP inhibitions of DNA polymerase, RNA polymerase and AMP pyrophosphorylase were discerned. Concentrations of MTI and c-MTIMP lower than 10^-3 M showed decreased feedback inhibition, but adenosine gave almost the same degree of feedback inhibition over a range of 10^-3 M to 10^-5 M.