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International Journal of Cell Cloning May 1990Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and... (Review)
Review
Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and therefore, a sensitive target of chemotherapy. Tiazofurin selectively blocks IMPDH activity. Tiazofurin was found to have an antiproliferative effect on tumor cells in vitro and in the murine system. Based on these findings, Phase I trials were started elsewhere in patients with solid tumors, but were discontinued because of toxicity. In leukemic patients, we were able to demonstrate a good correlation between biochemical parameters (i.e., decline in IMPDH activity and GTP concentrations in blast cells) and clinical response. The most consistent responses to therapy were seen in patients with myeloid blast crisis of chronic myeloid leukemia. Severe toxicity was seen in the earlier patients in the study. However, better patient selection, limitation of treatment duration and earlier recognition and treatment of complications have now made it possible to administer tiazofurin without undue toxicity.
Topics: Antineoplastic Agents; Drug Evaluation; Humans; IMP Dehydrogenase; Leukemia; Ribavirin; Ribonucleosides
PubMed: 2189014
DOI: 10.1002/stem.5530080303 -
Investigational New Drugs 1984Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma.... (Review)
Review
Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3-16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.
Topics: Animals; Antineoplastic Agents; Humans; Mice; Ribavirin; Ribonucleosides; Uric Acid
PubMed: 6381381
DOI: 10.1007/BF00173791 -
Advances in Enzyme Regulation 1990New 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... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Cell Line; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Oncogenes; Proto-Oncogenes; Ribavirin; Ribonucleosides; Tretinoin; Tumor Cells, Cultured
PubMed: 2206022
DOI: 10.1016/0065-2571(90)90007-o -
Investigational New Drugs May 1990Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to... (Review)
Review
Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (greater than or equal to grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 microM) and prolonged exposure to plasma levels exceeding 50 microM may result in a higher incidence of serious non-hematologic toxicity.
Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Evaluation; Female; Heart Diseases; Humans; Infusions, Intravenous; Leukopenia; Male; Nausea; Neoplasms; Ribavirin; Ribonucleosides; Ulcer; Vomiting
PubMed: 2200759
DOI: 10.1007/BF00177266 -
Biopharmaceutics & Drug Disposition 1987The pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the...
The pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the drug. The free fraction of tiazofurin was obtained from plasma by an ultrafiltration technique using a micropartition system. Total and free tiazofurin levels were determined by a sensitive high performance liquid chromatographic method. The percentage of tiazofurin bound to plasma proteins remained constant at approximately 15 per cent following administration to healthy mongrel dogs. The mean pharmacokinetic parameters of elimination rate constant (K), effective half-life (t 1/2), mean residence time (MRT) and the time to reach peak plasma level (tmax--after oral administration) were 0.32 +/- 0.04 h-1, 2.24 +/- 0.25 h, 3.23 +/- 0.36 h, and 1.78 +/- 0.50 h, respectively. The apparent volume of distribution at steady state was 0.98 +/- 0.30 1 kg-1 and the plasma clearance was 5.24 +/- 2.39 ml min-1 kg-1. About 90 per cent of tiazofurin was absorbed following oral administration. The pharmacokinetic parameters did not differ significantly between the total and free drug levels, indicating that the pharmacokinetics of total tiazofurin levels reflect those of the free tiazofurin in plasma.
Topics: Animals; Antineoplastic Agents; Dogs; Kinetics; Ribavirin; Ribonucleosides
PubMed: 3593893
DOI: 10.1002/bdd.2510080204 -
American Journal of Hematology Apr 1997Previous reports have established the synthesis of interleukin-6 (IL-6) and IL-6 receptors (IL-6R) in several human leukemia cells and found that IL-6 and the IL-6R...
Previous reports have established the synthesis of interleukin-6 (IL-6) and IL-6 receptors (IL-6R) in several human leukemia cells and found that IL-6 and the IL-6R could be expressed in cell lines with erythroid/megakaryocytic features. IL-6 is a pleiotropic cytokine involved in megakaryocytic differentiation. The finding that endogenous IL-6 levels in serum increased after 5-fluorouracil (5-FU) treatment suggests that IL-6 may play some role in the recovery of hematopoietic systems. This observation may assist the understanding of erythroid regeneration caused by antineoplastic agents such as tiazofurin. Tiazofurin inhibits the activity of IMP dehydrogenase. Its exposure to K562 cells at 10 microM tiazofurin stimulates erythroid differentiation. Stimulation of cells with tiazofurin gave a significant increase in IL-6 production. Its levels were quadrupled after 2 days of culture. Tiazofurin also caused a trivial reduction in the percentage of cells with the IL-6R. This evidence implies that tiazofurin produced no significant effect on the IL-6R. Tiazofurin also increased the percentage of benzidine-positive cells representing hemoglobin production, confirmed by GpA expression. We concluded that IL-6 is rate limiting in regard to hemoglobin production and that IL-3 could be used for clinical benefit to stimulate erythropoiesis and synergize with tiazofurin.
Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Hemoglobins; Humans; Interleukin-6; Leukemia; Ribavirin; Tumor Cells, Cultured
PubMed: 9092685
DOI: 10.1002/(sici)1096-8652(199704)54:4<301::aid-ajh7>3.0.co;2-z -
Journal of Medicinal Chemistry Mar 2016Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1'-cyano-2'-C-methyl-4-aza-7,9-dideazaadenosine... (Review)
Review
Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1'-cyano-2'-C-methyl-4-aza-7,9-dideazaadenosine C-nucleoside, have been recently described as effective against filovirus infections (Marburg) and hepatitis C virus (HCV), respectively. The first C-nucleoside analogues were described about half a century ago. The C-nucleoside pseudouridine is a natural component of RNA, and various other C-nucleoside analogues have been reported previously for their antiviral and/or anticancer potential, the most prominent being pyrazofurin, tiazofurin, and selenazofurin. In the meantime, showdomycin, formycin, and various triazole, pyrazine, pyridine, dihydroxyphenyl, thienopyrimidine, pyrazolotriazine, and porphyrin C-nucleoside analogues have been described. It would be worth revisiting these C-nucleosides and derivatives thereof, including their phosphoramidates, for their therapeutic potential in the treatment of virus infections and, where appropriate, cancer as well.
Topics: Adenine; Adenosine; Alanine; Animals; Antineoplastic Agents; Antiviral Agents; Humans; Nucleosides; Nucleotides; Pseudouridine; Purine Nucleosides; Pyrrolidines; Triazines
PubMed: 26513594
DOI: 10.1021/acs.jmedchem.5b01157 -
Cancer Research Feb 1986The exact route of metabolism of tiazofurin, a novel nucleoside with antitumor activity, is controversial. Using human cell lines severely deficient in salvage... (Comparative Study)
Comparative Study
The exact route of metabolism of tiazofurin, a novel nucleoside with antitumor activity, is controversial. Using human cell lines severely deficient in salvage nucleotide enzymes, we were able to identify the route of activation in tiazofurin metabolism. With loss of adenosine kinase activity by mutation in two lymphoblastoid cell lines, CCRF-CEM and WI-L2, the growth sensitivity to tiazofurin decreased by 6- and 3-fold, respectively. In contrast, the mutant lines were about 3000- to 1500- and 16- to 4-fold more resistant to the structurally similar tiazofurin analogues pyrazofurin and ribavirin, respectively. Other mutants with defective deoxycytidine or uridine kinase activity showed normal sensitivity to all three analogues. Both cell lines with defective adenosine kinase activity accumulated about 50% wild-type levels of tiazofurin-5'-monophosphate and thiazole-4-carboxamide adenine dinucleotide analogue of tiazofurin at cytotoxic concentrations of the drug. Extracts of wild-type lymphoblasts catalyzed the phosphorylation of tiazofurin in the presence of adenosine 5'-triphosphate and Mg2+. Loss of adenosine kinase activity in the mutant extract eliminated this phosphorylating activity for tiazofurin consistent with the notion that adenosine kinase catalyzes phosphorylation of tiazofurin. However, an enzyme activity that catalyzed the phosphorylation of tiazofurin in the presence of inosine-5'-monophosphate as donor and Mg2+ was detected in the extracts of both wild-type cells and adenosine kinase-deficient mutants. The monophosphate donor specificity, divalent metal, high salt requirement, and nucleoside acceptor specificity of this enzyme activity paralleled that of a 5'-nucleotidase (EC 3.1.3.5) which catalyzes inosine phosphorylation. In addition, tiazofurin phosphorylation was competitively inhibited by inosine and the apparent Ki value was similar to the apparent Km value for inosine phosphorylation. These results indicate that two enzymes, adenosine kinase and a cytoplasmic 5'-nucleotidase, are functionally important anabolizing enzymes for tiazofurin in human cells.
Topics: 5'-Nucleotidase; Adenosine Kinase; Adenosine Triphosphate; Amides; Biotransformation; Cell Line; Drug Resistance; Humans; Inosine Monophosphate; Lymphocytes; Nucleotidases; Phosphorylation; Phosphotransferases; Pyrazoles; Ribavirin; Ribonucleosides; Ribose; Substrate Specificity
PubMed: 3000575
DOI: No ID Found -
Journal of Medicinal Chemistry Dec 1997Tiazofurin, an important inhibitor of inosine 5'-monophosphate dehydrogenase, has been argued to possess a restricted glycosylic bond due to an energetically favorable...
Tiazofurin, an important inhibitor of inosine 5'-monophosphate dehydrogenase, has been argued to possess a restricted glycosylic bond due to an energetically favorable intramolecular (1-4) electrostatic interaction between the partial positive sulfur and the negative oxygen of the ribose. This rigidity has been appointed as a plausible cause that leads to activity in the sulfur containing compounds as opposed to the inactive oxazofurin-like analogues (i.e. S is replaced by an oxygen) that lack this favorable interaction. We reinvestigated this notion by using computational methods to report that although the above interaction (or its lack) is likely to contribute to the low-energy conformation of these classes of molecules, the flexibility of the glycosylic bond is ultimately determined by steric interaction of the heteroatoms with the C2'-H and O4' of the ribose. Application of this theory in the design of new analogues is presented as well.
Topics: Antimetabolites, Antineoplastic; Molecular Conformation; Ribavirin; Structure-Activity Relationship
PubMed: 9406604
DOI: 10.1021/jm970129s -
Cancer Letters Dec 1996Tiazofurin, a clinically active anticancer agent, is undergoing additional clinical testing in combination with other agents. We found that tiazofurin is an effective...
Tiazofurin, a clinically active anticancer agent, is undergoing additional clinical testing in combination with other agents. We found that tiazofurin is an effective biochemical modulator of 5-fluorouracil anabolism. Pretreatment of cultured L1210 cells with tiazofurin at concentrations of 1-100 microM results in an increase in the rate of conversion of 5-fluorouracil to phosphorylated metabolites. Concentrations of tiazofurin effective in increasing 5-fluorouracil anabolism cause a corresponding increase in the 5-phosphoribosyl-1-pyrophosphate pool. Studies in mice show that tiazofurin increases the lethal toxicity of 5-fluorouracil and increases the antitumor effectiveness of low doses of 5-fluorouracil: however, the combination is not more effective than an optimal dose of 5-fluorouracil given alone. These results indicate that caution should be exercised in the concurrent use of tiazofurin with other drugs, particularly 5-fluorouracil, that require 5-phosphoribosyl-1-pyrophosphate for activation or that are affected by a decrease in pyrimidine nucleotide synthesis.
Topics: Animals; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Induction; Fluorouracil; Leukemia L1210; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Phosphoribosyl Pyrophosphate; Ribavirin
PubMed: 9020902
DOI: 10.1016/s0304-3835(96)04416-3