Increased Inosinate Dehydrogenase Activity in Mycophenolic acid Resistant Neuroblastoma Cells

By incremental increase in the concentrations of inhibitors of essential biosynthetic pathways, a number of specific genes have been amplified in cultured mammalian cells. We have attempted to obtain an amplified phenotype by the progressive selection of resistance to mycophenolic acid, a potent inhibitor of the final two enzymes in guanine ribonuleotide synthesis, IMP dehydrogenase 1,2 and GMP synthetase2. In previous studies the inhibition of IMP dehydrogenase by mycophenolic acid has been shown to result in marked overproduction of purines in both human lymphoblasts 3,4 and mouse lyphoma cells5. Mycophenolic acid induced changes in ribonucleotide3,5,6 ’ and deoxyribonucleotide pools are well characterized. A mouse lymphoma line resistant to 20 μM mycophenolic acid has been obtained by sequential mutagenesis5 and single step mutagen induced resistant hamster V79 cells have also been obtained7