Mycophenolic acid and virazole are inhibitors of inosinate dehydrogenase and produce growth inhibition and loss of viability in cultured munine lymphoma L5178Y cells. Treat

Mycophenolic acid and virazole are inhibitors of inosinate dehydrogenase and produce growth inhibition and loss of viability in cultured munine lymphoma L5178Y cells. Treat ment with 1 @Mmycophenolic acid produced the following changes in concentrations of acid-soluble nucleotides: (a) guanosine tniphosphate decreased to less than 10% of con trol within 2 hr; (b) unidine triphosphate and cytidine tn phosphate concentrations increased markedly; (C) adeno sine triphosphate did not change; (d) deoxyguanosine tn phosphate decreased; and (e) thymidine triphosphate in creased. DNA synthesis was inhibited by 90% within 2 hm, whereas the incorporation of adenosine into RNA and of leucine into protein were much less affected. Virazole (100 @M)produces similar effects. These biochemical effects of mycophenolic acid, as well as its effects on cell growth, can be prevented by addition of guanylate to the medium. Myco phenolic acid treatment also appears to cause breakdown of high-molecular-weight DNA.