Novel nucleoside inhibitors of guanosine metabolism as antitumor agents

Abstract

A detailed study of the inhibition of DR and TR in the SkLu-1 line of human lung adenocarcinoma has shown that TR significantly inhibits this tumor line, probably via inhibition of IMP dehydrogenase by the corresponding TAD analog of NAD. DR exhibited a similar degree of inhibition in this cell line. In a system devised to detect the inhibition of cloning efficiency of the SkLu cells, DR showed a 50% inhibition at 4 X 10(-3) M and TR at 1 X 10(-4) M. When DR and TR were used in combination, the ID50 was decreased to 3 X 10(-5) M. The study of DR in a number of human carcinoma cell lines revealed that de novo purine biosynthesis was significantly inhibited; however, in the SkLu-1 lung carcinoma cells this inhibition was not observed. The synergism observed in this cell line is presently viewed as potentially due to both agents acting on IMP dehydrogenase at different sites.