SYNERGISTIC ACTION OF TIAZOFURIN WITH HYPOXANTHINE AND ALLOPURINOL INHUMAN NEUROECTODERMAL TUMOR-CELL LINES

The activity of IMP dehydrogenase (EC 1.2.1.14), the key enzyme of de novo guanylate biosynthesis, was shown to be increased in tumor cells. Tiazofurin (TR), a potent and specific inhibitor of this enzyme, prov ed to be effective in the treatment of refractory granulocytic leukemi a in blast crisis. We examined the effects of tiazofurin as a single a gent and in combination with hypoxanthine and allopurinol in six diffe rent neuroectodermal tumor cell lines. the STA-BT-3 and 146-18 human g lioblastoma cell lines, the SK-N-SH, LA-N-1 and LA-N-5 human neuroblas toma cell lines, and the STA-ET-1 Ewing tumor cell line. Tiazofurin in hibited tumor cell growth with IC50 values between 2.2 mu M (LA-N-1 ce ll line) and 550 mu M (LA-N-5 cells) and caused a significant decrease of intracellular GTP pools (GTP concentrations decreased to 39-79% of control). Incorporation of [8-C-14]guanine into GTP pools was determi ned as a measure of guanylate salvage activity; incubation with 100 mu M hypoxanthine caused a 62-96% inhibition of the salvage pathway. Inc ubation with tiazofurin (100 mu M) and hypoxanthine (100 mu M) synergi stically inhibited tumor cell growth, and the addition of allopurinol (100 mu M) strengthened these effects. Therefore, this drug combinatio n, inhibiting guanylate de novo and salvage pathways, may prove useful in the treatment of human neuroectodermal tumors.