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, proved to be effective in the treatment of refractory
granulocytic leukemia in
blast crisis. We examined the effects of
tiazofurin as a single agent and in combination with
hypoxanthine and
allopurinol in six different
neuroectodermal tumor cell lines, the STA-BT-3 and 146-18 human
glioblastoma cell lines, the SK-N-SH, LA-N-1 and LA-N-5 human
neuroblastoma cell lines, and the STA-ET-1
Ewing tumor cell line.
Tiazofurin inhibited
tumor cell growth with IC50 values between 2.2 microM (LA-N-1 cell line) and 550 microM (LA-N-5 cells) and caused a significant decrease of intracellular
GTP pools (
GTP concentrations decreased to 39-79% of control). Incorporation of [8-14C]
guanine into
GTP pools was determined as a measure of guanylate salvage activity; incubation with 100 microM
hypoxanthine caused a 62-96% inhibition of the salvage pathway. Incubation with
tiazofurin (100 microM) and
hypoxanthine (100 microM) synergistically inhibited
tumor cell growth, and the addition of
allopurinol (100 microM) strengthened these effects. Therefore, this
drug combination, inhibiting guanylate de novo and salvage pathways, may prove useful in the treatment of human
neuroectodermal tumors.