Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some of the current critical issues in the tiazofurin treatment of end-stage leukemia were presented and discussed. 1. Tiazofurin infusions (daily X 10 to 15) provided remissions in 50% of end-stage leukemic patients. The remissions, of 1 to 10 months' duration, varied from antileukemic effect or hematologic improvement to complete response and complete remission. The total survival of the responding patients was from about 1 to 15 months. 2. Our administration of tiazofurin in a 60-min infusion by pump decreased the incidence and severity of toxicity. 3. It was shown that tiazofurin dose does not need to be escalated at each relapse. Depending on the biochemical and hematological response in this novel protocol, 2,200 to 4,400 mg/m2 tiazofurin appeared to be sufficient to provide remissions. 4. A new role was identified for allopurinol, originally given to decrease uric acid in the plasma. Allopurinol markedly increased plasma hypoxanthine concentrations which competitively inhibited the activity of the salvage enzyme, guanine phosphoribosyltransferase, in the blast cells. Thus, the elevated hypoxanthine plasma levels inhibited guanine salvage. To maintain high hypoxanthine levels allopurinol (100 mg) was given every 4 to 6 hr. This provided combination chemotherapy with tiazofurin which inhibited IMP dehydrogenase activity and blocked the de novo biosynthesis of guanylates in the blast cells. 5. Preliminary evidence was obtained in the patients that tiazofurin induced differentiation of the bone marrow. Recent studies also showed that tiazofurin down-regulated the expression of the c-Ki-ras oncogene in K562 erythroleukemic cells. Therefore, tiazofurin treatment provides an impact by chemotherapy, induced differentiation, and, if applicable, through down-regulation of the ras oncogene. 6. Novel aspects of tiazofurin treatment include rational targeting and a continuously monitored trial by measurement of the activity of IMP dehydrogenase and of GTP and TAD concentrations in blast cells and of tiazofurin and hypoxanthine in plasma. 7. Since tiazofurin has not yet achieved lasting remissions in patients nor terminal differentiation of leukemic cells it probably will be advantageous to combine tiazofurin with other drugs to provide synergism. In preclinical tissue culture studies in HL-60 cells synergy was observed with retinoic acid. This may be of interest because retinoic acid also caused differentiation and down-regulation of the myc oncogene.
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PMID:Critical issues in chemotherapy with tiazofurin. 269 55

Tiazofurin, an anticancer drug which inhibits IMP dehydrogenase, decreases cellular GTP concentration, induces differentiation and down-regulates ras and myc oncogene expression, caused apoptosis of K562 cells in a time- and dose-dependent fashion. Apoptotic cells were detected by (1) flow cytometry, (2) electron microscopy, and (3) fluorescence in situ nick translation and confocal microscopy, while the DNA ladder was not detectable. The induced apoptosis was abrogated by guanosine which replenishes GTP pools through the guanosine salvage pathways, while it was enhanced by hypoxanthine, a competitive inhibitor of GPRT. The tiazofurin-mediated apoptosis may therefore be linked with the decrease of GTP and the consequent impairment of specific signal transduction pathways. Tiazofurin induced apoptosis also in lymphoblastic MOLT-4 cells, suggesting that this action is not confined to cells of the myeloid lineage, where the differentiating effects of the drug are more pronounced.
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PMID:IMP dehydrogenase inhibitor, tiazofurin, induces apoptosis in K562 human erythroleukemia cells. 905 44

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80