An overview was presented of our approach of inhibition of de novo and salvage pathways in
pyrimidine and
purine metabolism. 1. Combination of
acivicin, an inhibitor of de novo biosynthesis, and
dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in
hepatoma and colon
carcinoma cells. 2. AZT, a competitive inhibitor of the salvage
enzyme,
thymidine kinase, and
5-FU or MTX provided synergistic cytotoxicity in
hepatoma 3924A. In human colon
carcinoma HT-29 cells AZT and
methotrexate yielded synergistic cytotoxicity and
thymidine and
hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat
hepatoma 3924A and in human cell lines HT-29, HL-60 and K562
thymidine kinase activity was 16- to 67-fold higher than that of
dTMP synthase. Therefore, inhibition of
dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with
tiazofurin, an inhibitor of
IMP dehydrogenase, the rate-limiting
enzyme of
GTP biosynthesis, and with
allopurinol, which inhibits GPRT activity through raising plasma
hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in
IMP dehydrogenase activity and
GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by
tiazofurin through the decrease of
GTP concentration has now been shown in K562, HL-60 and
hepatoma cells and in patients with
chronic granulocytic leukemia in
blast crisis.
Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to
tiazofurin treatment. From this group, 10 out of 12 patients (83%) with
chronic granulocytic leukemia in
blast crisis responded to
tiazofurin treatment.