Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin (TR), an inhibitor of IMP dehydrogenase, causes remissions and induced differentiation in human leukemia through lowering the concentrations of GTP and dGTP. A deoxycytidine analog, difluorodeoxycytidine (DFDC), is an anti-tumor agent phosphorylated by deoxycytidine kinase, resulting in decreased concentration of dCTP, leading to inhibition of DNA synthesis. In HL-60 cells DFDC induced differentiation and inhibited proliferation in a dose-dependent manner (IC50 = 4 nM); TR provided synergism with DFDC. DFDC inhibited proliferation in OVCAR-5 human ovarian carcinoma cells (IC50 = 25 nM) and colony formation in PANC-1 human pancreatic carcinoma cells (IC50 = 2 nM) and rat hepatoma 3924A cells (IC50 = 22 nM). TR and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells. The two drugs together should be helpful in treating leukemias and solid tumors in humans.
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PMID:Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity. 134 74

Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 microM, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 microM and an IC50 of 29 microM being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.
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PMID:Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells. 145 Dec 38

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.
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PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

There was an overexpression of the c-myc gene (11-fold) and of the c-Ha-ras gene (2-fold) in rat hepatoma 3924A cells compared to normal rat liver as measured by dot-blot analysis of total cytoplasmic RNA. The overexpression of c-myc was attributed to a 10- to 14-fold amplification and rearrangement of the c-myc sequences as determined by Southern blot analysis. The expression of the c-myc also was dependent upon the proliferative state of the hepatoma cells. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide; NSC 286193), an inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of GTP biosynthesis, resulted in a rapid drop (less than 1 h) to 50% of control in the target enzyme activity in the hepatoma cells and in a subsequent marked decrease to 55% in GTP concentration. These events were followed at 12 h of tiazofurin treatment by a 3-fold reduction in the expression of the c-myc gene and a 9-fold decline in that of the c-Ha-ras gene. These results in the hepatoma cells provide evidence in support of the earlier demonstrated correlation in K562 cells between GTP concentration and expression of c-myc and c-ras genes (Olah et al., 1989). These genes might depend on GTP for their expression in hepatoma cells and they might cooperate in a signal pathway that controls cell proliferation.
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PMID:Down-regulation of c-myc and c-Ha-ras gene expression by tiazofurin in rat hepatoma cells. 197 79

New light was thrown on the action of tiazofurin in the treatment of end-stage leukemic patients and in leukemic cells in tissue culture. 1. In a population of 21 consecutive patients 50% responded to tiazofurin treatment, confirming the usefulness of this therapy in end-stage leukemia. 2. In leukemic patients treated with tiazofurin and allopurinol reciprocal action was manifested in the increase in hypoxanthine and the decrease in uric acid concentrations in the plasma. On discontinuation of allopurinol, hypoxanthine levels steeply declined but uric acid concentration increased slowly, taking days to reach pretreatment level. 3. With a new and sensitive method the concentration of the active metabolite of tiazofurin, TAD, was measured in the mononuclear cells of tiazofurin-treated patients. Approximately 5 to 13% of the plasma tiazofurin level was observed as TAD in the mononuclear cells. This TAD concentration was sufficient to account for the inhibition of IMP DH in these cells. 4. Tiazofurin or retinoic acid caused differentiation of HL-60 leukemic cells and inhibition of cell proliferation. 5. By treating leukemic cells incubated with tiazofurin or retinoic acid also with guanosine it was elucidated that the mechanism of the two drugs differed since only the tiazofurin effects were counteracted by guanosine. 6. Tiazofurin and retinoic acid together in HL-60 cells provided synergistic impact on differentiation and cytotoxicity. 7. Tiazofurin resulted in down-regulation of the expression of ras and myc oncogenes in three systems: K562 human erythroleukemic cells, rat hepatoma 3924A cells and human HL-60 leukemia cells. 8. Because both tiazofurin and retinoic acid are licensed drugs, their potential use in combination chemotherapy may have clinical relevance in the treatment of end-stage leukemia where our earlier studies have demonstrated the usefulness of tiazofurin.
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PMID:Tiazofurin action in leukemia: evidence for down-regulation of oncogenes and synergism with retinoic acid. 220 22

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurements of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chest and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on a weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.
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PMID:Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. 234 2

The molecular correlation concept proposed that IMP dehydrogenase activity should be a sensitive target of chemotherapy. This hypothesis received support from an array of evidence. IMP dehydrogenase has the lowest activity in purine biosynthesis; it is the rate-limiting enzyme in GTP production; the enzymic activity is transformation-and progression-linked; it is elevated in all examined animal and human neoplastic cells. The activity of GMP synthetase and the concentrations of GMP and dGTP were increased in cancer cells. Whereas guanine salvage has a high potential activity, the low guanine content may well curtail actual salvage capacity. Ribonucleotide reductase activity was two orders of magnitude lower than that of IMP dehydrogenase. Tiazofurin, a C-nucleoside, had marked cytotoxicity on hepatoma cells in vitro and was the first drug that as a single agent profoundly inhibited the proliferation of the subcutaneously inoculated solid hepatoma 3924A in the rat. The impact of tiazofurin administration in hepatoma cells was revealed in a cascade of biochemical alterations involving primary, secondary and tertiary targets and markers of this drug action. The primary target was IMP dehydrogenase where the active metabolite of tiazofurin, TAD, was thought to be absorbed to the NADH site of the enzyme. As a consequence, the enzymic activity declined rapidly to about 30-40% and returned to normal range by 36 to 48 hr after injection. The secondary targets and markers are the profoundly decreased pools of guanylates (GMP, GDP, GTP). Concurrently, the concentrations of IMP and PRPP were increased 8- to 15-fold. The elevated IMP pools were attributed to the de-inhibition of the AMP deaminase activity subsequent to the decline in GTP concentration. The rise in PRPP pools was attributed to the selective inhibition of GPRT and HPRT activities by the high IMP pool which did not affect APRT activity. This interpretation is supported by the 6- to 8-fold increase in the concentrations of guanine and hypoxanthine and the lack of change in the adenine pools inthe hepatomas after tiazofurin administration. The marked drop in NAD concentration which was drug dose- and time-dependent is attributed to the competition for NAD pyrophosphorylase activity by the precursors of NAD and tiazofurin monophosphate. The tertiary targets were dominated by the profound alterations in the concentrations of the dNTPs. This was characterized by a rapid and persistent drop (for 3 days) of the dGTP pool. The concentrations of dATP and dCTP also declined, but these alterations were less pronounced and the pools returned to normal after 2 days.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Targets and markers of selective action of tiazofurin. 242 86

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC-286193) has shown potent cytotoxic and antitumor activity against hepatoma 3924A carried in the rat [Lui et al. J. biol. Chem. 259, 5078 (1984)]. However, eventually the tumor emerged, proliferated and killed the host. To throw light on the factors that play a role in the resistance to this drug, a tiazofurin-induced resistant hepatoma 3924A line in culture was produced, and its biochemical and pharmacological pattern was examined. Resistance in hepatoma cells was expressed by a reprogramming of gene expression that entailed the display of a program of multiple biochemical alterations. In the resistant cells the activity of IMP dehydrogenase, the target enzyme of tiazofurin, was increased 2- to 3-fold. The steady-state guanylate pools were elevated 3-fold, and there was a decrease in the de novo synthesis of guanylate. There was an expansion of guanylate salvage, which could circumvent inhibition of de novo guanylate synthesis by tiazofurin. For the first time in studies on the resistance of different cell lines to tiazofurin, reduced tiazofurin transport (to 50%) in resistant hepatoma cells was identified which might account for the decreased concentration (50%) of the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), in these cells. NAD pyrophosphorylase activity also decreased to 53% of that of the sensitive line, which was responsible, in part at least, for the decreased TAD concentration of the resistant cells. When resistant cells were cultured in the absence of tiazofurin, resistance to the drug gradually decreased, and by 50 passages sensitivity returned. Resistance to tiazofurin in hepatoma cells appears to be a drug-induced metabolic adaptation which involves alterations in the activity of the target enzyme, in the transport and concentration of the drug and the active metabolite, and an increase of guanylate concentration and guanine salvage capacity.
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PMID:Mechanism of resistance to tiazofurin in hepatoma 3924A. 286 29

Tiazofurin, an anti-cancer drug, which induces remissions in human leukemia, and ribavirin, an anti-viral agent, bind at separate sites (NADH and IMP-XMP sites, respectively) on the target enzyme, IMP dehydrogenase. Now we show that the binding to IMP dehydrogenase of these drugs at two separate sites is translated into synergistic inhibition of de novo guanylate biosynthesis and synergistic toxicity in rat hepatoma 3924A cells. These results may be utilized in the chemotherapy of neoplastic diseases and in the treatment of hepatitis virus infection and hepatocellular carcinoma.
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PMID:Synergistic cytotoxic effect of tiazofurin and ribavirin in hepatoma cells. 289 52

The hypothesis was tested that the increased IMP dehydrogenase activity in human myelocytic leukemic cells, and along with it guanylate biosynthesis, might be a sensitive target to chemotherapy by tiazofurin. 1. IMP dehydrogenase activity in normal leukocytes was 3.1 +/- 0.5 (means +/- S.E.) nmol/hr/mg protein and in leukemic cells it was elevated 15- to 41-fold. The activity of guanine phosphoribosyltransferase in normal leukocytes was 389 +/- 27 nmol/hr/mg protein and in the leukemic cells it increased 2.8- to 6.8-fold. 2. IMP dehydrogenase was purified 4,900-fold to homogeneity from rat hepatoma 3924A with a yield of 30%. The kinetic properties of the hepatoma enzyme were similar to those of the enzyme in human myelocytic leukemic blast cells because of the similarity of the Km's for IMP (23 microM), NAD (44 and 65 microM); the Ki for TAD was 0.1 microM in both enzymes. 3. There was a selectivity of the in vitro response to tiazofurin in human normal and leukemic leukocytes. When labeled tiazofurin was incubated with leukocytes from normal, healthy volunteers and from leukemic patients, the leukemic leukocytes made 20- to 30-fold more TAD and the GTP content decreased as compared to normal leukocytes. This procedure proved to be a suitable predictive test in a clinical setting because patients with positive tests responded to tiazofurin whereas those with negative ones did not. 4. The National Cancer Institute approved a chemotherapeutic phase I/II trial which concentrates on treatment of refractory acute myelocytic leukemia. Tiazofurin is infused in a 60-minute period with a pump to insure uniform delivery. A novel aspect of the trial was that it was directed primarily by the biochemical impact of tiazofurin on IMP dehydrogenase activity and GTP concentration and the tiazofurin doses were to be adjusted accordingly. Patients received allopurinol as a routine precaution against possible accumulation of uric acid in the kidney. 5. In the first eight patients, there was one complete remission, two entered the chronic phase, two entered into partial remission, one did not respond, and two were not evaluable. In the five patients who responded, there was a rapid, profound decrease in IMP dehydrogenase activity of the blast cells and a gradual decline in GTP concentrations. The blast cell count followed the decrease in the GTP concentration. The white blood cell count was largely preserved. 6. Bone marrow aspirates and peripheral blood samples showed that with tiazofurin treatment there was an induced differentiation of the myelocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukemia. 290 68


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