The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
George Weber - One of the best experts on this subject based on the ideXlab platform.
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Synergistic down-regulation of signal transduction and cytotoxicity by Tiazofurin and quercetin in human ovarian carcinoma cells.
Life sciences, 1999Co-Authors: Fei Shen, Maria Herenyiova, George WeberAbstract:Abstract Ovarian carcinoma is one of the most common causes of cancer death in women. Tiazofurin, a C-nucleoside, arrests the cell cycle at S phase and reduces the activities of PI (phosphatidylinositol) utilizing enzymes in signal transduction by depleting cellular GTP concentration. Quercetin (QN), a flavonoid, attacks the cell cycle at the G 1 and S phase boundary and mainly inhibits PI kinase (1-phosphatidylinositol 4-kinase, EC 2.7.1.67) activity in the signal transduction pathway. Because Tiazofurin and QN attack different biochemical targets and arrest different phases of the cell cycle, we tested the hypothesis that the two drugs might be synergistic against human carcinoma cells. In human ovarian carcinoma OVCAR-5 cells in growth inhibition assay, the IC 50 s (drug concentration that inhibits 50% of cell proliferation) for Tiazofurin and QN were (mean ± SE) 13 ± 1.2 and 66 ± 3.0 μM; in clonogenic assays they were 6 ± 0.5 and 15 ± 1.2 μM, respectively. When Tiazofurin was added to cells followed 12 h later by QN, synergism was observed in both growth inhibition and clonogenic assays. The combination also yielded synergistic reduction of IP 3 (inositol 1,4,5-trisphosphate) concentration in the cells which may explain, at least in part, the synergistic action of Tiazofurin and QN in OVCAR-5 cells. The protocols yielding synergism may have implications in the clinical treatment of human ovarian carcinoma.
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Synergistic action of Tiazofurin and genistein on growth inhibition and differentiation of K-562 human leukemic cells
Life sciences, 1998Co-Authors: George WeberAbstract:Abstract Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), an oncolytic drug, inhibits IMP DH (inosine 5′-monophosphate dehydrogenase, EC 1.1.1.205), reduces signal transduction activity and IP3 (inositol 1,4,5-trisphosphate) concentration and arrests the cell cycle chiefly in S phase. Genistein (4′,5,7-trihydroxyisoflavone), an inhibitor of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase, EC 2.7.1.68), tyrosine kinase and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both drugs, as single agents, induce differentiation. Since Tiazofurin and genistein attack different enzymic targets and arrest the cell cycle at different phases and they each induce differentiation, we tested the hypothesis that Tiazofurin might be synergistic with genistein in inducing differentiation. Human leukemic K-562 cells were grown in suspension culture and were seeded in 24-well culture plates. In growth inhibition assays for Tiazofurin and genistein IC50s (drug concentration that inhibits 50% of cell proliferation) were 7 and 37 μM, respectively. For Tiazofurin and genistein the concentrations of drug that induce differentiation in 50% of the cells were 35 and 45 μM, respectively. Various combinations of these two drugs were tested. Since Tiazofurin decreased GTP concentration in cells by 50% at 12 hr after administration, genistein (10 to 30 μM) was added 12 hr after Tiazofurin (5 to 15 μM). Synergistic action on differentiation was obtained from all Tiazofurin and genistein combinations and in most combinations on growth inhibition. The percent of differentiating cells induced by genistein (10 μM) and Tiazofurin (10 μM) as single agents increased 1.1- and 2.8-fold, respectively, of the control values. The two drugs together caused 5.9-fold elevation in inducing differentiation. Similar action was observed on inhibition of proliferation.
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IMP dehydrogenase inhibitor, Tiazofurin, induces apoptosis in K562 human erythroleukemia cells
Cytometry, 1997Co-Authors: Marco Vitale, Loris Zamai, Elisabetta Falcieri, Giorgio Zauli, Pietro Gobbi, Spartaco Santi, Caterina Cinti, George WeberAbstract: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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Molecular mechanisms in the antiproliferative action of taxol and Tiazofurin
Anticancer research, 1996Co-Authors: Edith Olah, Noemi Prajda, Bela Csokay, Zsofia Kote-jarai, Y A Yeh, George WeberAbstract:The molecular antiproliferative effects of taxol and Tiazofurin were studied in human K562 leukemia, and in MCF-7 breast and OVCAR-5 ovarian carcinoma cell cultures. A single treatment with taxol (2 to 100 nM) or Tiazofurin (5 to 20 microM) on K562 leukemia cells resulted in both a differentiation program and apoptosis in the same cell culture. Tiazofurin proved to be the most potent inducer of differentiation among the inducers, however, taxol had a major impact on induction of the alterations characteristic of apoptosis. The antiproliferative effect of Tiazofurin was mediated by 37 to 85% inhibition of IMP dehydrogenase activity. Both the differentiation and apoptosis induced by Tiazofurin were dependent on GTP supply. The induction of differentiation and/or apoptosis was mediated by downregulation of c-myc and Ki-ras oncogenes in all three cell lines treated with Tiazofurin (by 2 hr) or taxol (by 24 hr). Combined treatments with Tiazofurin and taxol exerted a schedule-dependent, antiproliferative interaction in the cell lines studied. Synergistic inhibition of cell proliferation was observed when cells were pretreated with Tiazofurin (10 to 15 microM) for at least 12 hr, then taxol (5 to 15 nM) was added.
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Tiazofurin: molecular and clinical action.
Anticancer research, 1996Co-Authors: George Weber, Noemi Prajda, M. Abonyi, Katherine Y. Look, G TricotAbstract:The purpose is to provide an overview of the molecular and clinical impact of Tiazofurin. Method. The biochemical and clinical techniques were reported (1, 2). Results. IMP DH activity increased in various animal and human tumors and was particularly high in leukemic blast cells. The increased activity was due to an elevation in the mRNA concentration of type ll isozyme. Tiazofurin, a C-nucleoside, was converted in sensitive cells to the active metabolite, TAD, which tightly bound at the NADH site inhibited IMP DH activity. The inhibition led to decreased GTP concentration, down-regulation of ras and myc oncogenes and induced maturation of blast cells. New evidence shows that Tiazofurin injection downregulated signal transduction activity due to a reduction of the activities of PI and PIP kinases leading to a decrease in the concentration of the second messenger, IP 3 . In patients, Tiazofurin infusion and allopurinol administration led to reduction of IMP DH activity and GTP concentration. Allopurinol inhibited xanthine oxidase activity leading to a marked rise in hypoxanthine concentration which inhibited the increased guanine salvage pathway. In the clinic, the increase in serum hypoxanthine concentration is essential for the success of Tiazofurin treatment. Tiazofurin showed additivity or synergism with ribavirin, retinoic acid, taxol, quercetin, gemcitabin, dipyridamole and brefeldin. Ribavirin which inhibits IMP DH at the IMP site has been shown to prolong the IMP depressing action of Tiazofurin in rat bone marrow cells. Conclusion. Tiazofurin and allopurinol achieve reduction of GTP concentration in leukemic blast cells through inhibition of IMP DH and GPRT activities. As a result, induced maturation occurs with down-regulation of ras and myc oncogenes and probably reduced signal transduction capacity. Tiazofurin in leukemic patients provides over 75% therapeutic responses and patients can be treated with this combination for many months with good quality of life. These clinical and biochemical results were recently confirmed independently (3).
Hiremagalur N. Jayaram - One of the best experts on this subject based on the ideXlab platform.
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Relationships Between the Cytotoxicity of Tiazofurin and Its Metabolism by Cultured Human Lung Cancer Cells
2016Co-Authors: Desmond N. Camey, Hiremagalur N. Jayaram, David A. Cooney, Gurpreet S. Ahluwalia, David G. JohnsAbstract:The antitumor activity of the antineoplastic agent, Tiazofurin (2-,jD-ribofuranosylthiazole-4-carboxamide), has previously been shown to require intracellular anabolism of the drug to a nicotinamide adenine dinucleotide (NAD) analog (2-f-D-ribofuranosylthiazole-4-carboxamide adenine dinucleotide or "Tiazofurin adenine dinucleotide"), which then acts as a potent inhibitor of the target enzyme inosine monophosphate (IMP) dehydrogenase. Inhibition of the latter enzyme in turn brings about a profound depletion of intracellular guanosine nucleotides essential for tumor cell growth and replication. In the present study, the cytotoxicity and metabolism of Tiazofurin have been examined in six human lung cancer cell lines. At the pharma-cologically attainable drug concentration of 100 AM, colony survival was <1.5 % in three cell lines ("sensitive"), whil
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A New Tiazofurin Pronucleotide: Synthesis and Biological Evaluation of cycloSaligenyl‐Tiazofurin Monophosphate
ChemInform, 2004Co-Authors: Loredana Cappellacci, Hiremagalur N. Jayaram, Palmarisa Franchetti, G. Barboni, Claudia Martini, Mario GrifantiniAbstract:Synthesis and biological activities of cyclosaligenyl-Tiazofurin monophosphate (CycloSal-TRMP), a new Tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.
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A New Tiazofurin Pronucleotide: Synthesis and Biological Evaluation of CycloSaligenyl-Tiazofurin Monophosphate
Nucleosides nucleotides & nucleic acids, 2003Co-Authors: Loredana Cappellacci, Hiremagalur N. Jayaram, Palmarisa Franchetti, G. Barboni, Claudia Martini, Mario GrifantiniAbstract:Synthesis and biological activities of cyclosaligenyl-Tiazofurin monophosphate (CycloSal-TRMP), a new Tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.
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Biochemical consequences of resistance to Tiazofurin in human myelogenous leukemic K562 cells.
Cancer Research, 1993Co-Authors: Hiremagalur N. Jayaram, Weining Zhen, Kamran GharehbaghiAbstract:Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, Tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to Tiazofurin were developed by drug-selection pressure. Compared to a concentration producing 50% cell proliferation reduction that was 9.1 µm in sensitive cells, the resistant variants displayed concentrations producing 50% cell proliferation reductions of 12 and 16 mm. The activity of the target enzyme, IMP dehydrogenase, was not altered in the resistant cells. Studies on Tiazofurin metabolism revealed that resistant variants formed
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Clinical pharmacokinetic study of Tiazofurin administered as a 1-hour infusion
International journal of cancer, 1992Co-Authors: Hiremagalur N. Jayaram, Guido Tricot, Ronald Hoffman, Elizabeth Lapis, Weining Zhen, Edith Paulik, Patricia Kneebone, George P. Engeler, George WeberAbstract:Tiazofurin, 2-β-d-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with Tiazofurin with I-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 Tiazofurin peak plasma concentrations were 245, 441 and 736 μM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our I -hr infusion method, biphasic pharmacokinetics were noted with αt1/2 and βt1/2 of 0.5 and 6.2 hr, and Tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our I -hr infusion was 52% of that reported for the same dose given by continuous infusion. Our I -hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of Tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using I -hr infusion may be feasible for other carefully selected types of malignancies.
Mario Grifantini - One of the best experts on this subject based on the ideXlab platform.
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A New Tiazofurin Pronucleotide: Synthesis and Biological Evaluation of cycloSaligenyl‐Tiazofurin Monophosphate
ChemInform, 2004Co-Authors: Loredana Cappellacci, Hiremagalur N. Jayaram, Palmarisa Franchetti, G. Barboni, Claudia Martini, Mario GrifantiniAbstract:Synthesis and biological activities of cyclosaligenyl-Tiazofurin monophosphate (CycloSal-TRMP), a new Tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.
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A New Tiazofurin Pronucleotide: Synthesis and Biological Evaluation of CycloSaligenyl-Tiazofurin Monophosphate
Nucleosides nucleotides & nucleic acids, 2003Co-Authors: Loredana Cappellacci, Hiremagalur N. Jayaram, Palmarisa Franchetti, G. Barboni, Claudia Martini, Mario GrifantiniAbstract:Synthesis and biological activities of cyclosaligenyl-Tiazofurin monophosphate (CycloSal-TRMP), a new Tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.
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Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents.
Current medicinal chemistry, 1999Co-Authors: Palmarisa Franchetti, Mario GrifantiniAbstract:IMP dehydrogenase (IMPDH) is an enzyme which catalyzes the NAD-dependent conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) at the metabolic branch point in the de novo purine nucleotide synthetic pathway. IMPDH was shown to be increased significantly in cancer cells and therefore considered to be a sensitive target for cancer chemotherapy. By blocking the conversion of IMP to XMP, IMPDH inhibitors lead to depletion of the guanylate (GMP, GDP, GTP and dGTP) pools. Two isoforms of human IMPDH, designed type I and type II, have been identified and sequenced. Type I is constitutively expressed and is the predominant isoform in normal cells, while type II is selectively up-regulated in neoplastic and replicating cells. Two types of IMPDH inhibitors, endowed with antineoplastic, antiviral and immunosoppressive activity, have been discovered so far: nucleoside inhibitors, such as ribavirin and Tiazofurin, and non-nucleoside, such as mycophenolic acid. Ribavirin produces IMPDH inhibition via its anabolite 5'-monophosphate. Tiazofurin inhibits the enzyme after metabolic conversion into thiazole-4-carboxamide adenine dinucleotide (TAD), an analogue of the cofactor NAD. It was hypothesized that the inhibitory activity of Tiazofurin is due to an attractive electrostatic interaction between the heterocyclic sulphur atom and the furanose oxygen 1' which constrain rotation about the C-glycosidic bond in Tiazofurin and in its active anabolite TAD. To check this hypothesis, we studied several C-nucleosides related to Tiazofurin and their NAD analogues. Non-nucleoside IMPDH inhibitors are also reviewed.
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C-glycosyl bond conformation in oxazofurin : crystallographic and computational studies of the oxazole analogue of Tiazofurin
Journal of medicinal chemistry, 1994Co-Authors: Barry M. Goldstein, Palmarisa Franchetti, Loredana Cappellacci, Wendy H. Hallows, David A. Langs, Mario GrifantiniAbstract:Oxazofurin is the inactive oxazole analogue of the C-glycosyl thiazole antitumor agent Tiazofurin. Replacement of the thiazole sulfur in Tiazofurin with the oxazole oxygen in oxazofurin produces conformational effects that are examined using crystallographic and computational methods. The crystal structure of oxazofurin contains six molecules in the asymmetric unit and has been refined to a standard R value of 6.8% for all data. The six oxazofurin conformers show an average C-glycosidic torsion angle of 70(9) degrees. This value is significantly higher than the average absolute C-glycosidic torsion angle of 24(10) degrees obtained from previous thiazole nucleoside structures. Previous studies suggest that, in Tiazofurin, an electrostatic interaction between a positively charged thiazole sulfur and negatively charged furanose oxygen constrains the C-glycosidic torsion angle to a relatively small value. Ab initio molecular orbital studies presented here suggest that the higher C-glycosidic angles observed in the oxazofurin structures result from a repulsive interaction between negatively charged oxazole and furanose oxygens. Thus, it is likely that differences in activity between oxazo- and Tiazofurin are either (1) due directly to differences in electronic properties between the thiazole and oxazole rings or (2) due to the variation in C-glycosidic bond conformation resulting from the alteration in the charge distribution of the heterocycle.
Velimir Popsavin - One of the best experts on this subject based on the ideXlab platform.
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antitumour Tiazofurin analogues embedded with an amide moiety at the c 2 position
Tetrahedron, 2011Co-Authors: Mirjana Popsavin, Miloš Svirčev, Dimitar Jakimov, Ljilja Torovic, Gordana Bogdanovic, Vesna Kojic, Sasa Spaic, Lidija D Aleksic, Velimir PopsavinAbstract:Abstract Synthesis of four new Tiazofurin analogues has been accomplished starting from d -glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3- O -acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected Tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of Tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (Tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b – d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d , while HeLa cells were sensitive to 2a , 2b and 2d . Only analogue 2a was highly cytotoxic against MCF-7 cells. No Tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of Tiazofurin analogues 2a – d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, Tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.
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Antitumour Tiazofurin analogues embedded with an amide moiety at the C-2′ position
Tetrahedron, 2011Co-Authors: Mirjana Popsavin, Miloš Svirčev, Ljilja Torović, Gordana Bogdanović, Vesna Kojić, Dimitar Jakimov, Saša Spaić, Lidija D. Aleksić, Velimir PopsavinAbstract:Abstract Synthesis of four new Tiazofurin analogues has been accomplished starting from d -glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3- O -acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected Tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of Tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (Tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b – d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d , while HeLa cells were sensitive to 2a , 2b and 2d . Only analogue 2a was highly cytotoxic against MCF-7 cells. No Tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of Tiazofurin analogues 2a – d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, Tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.
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2 3 amino 3 deoxy β d xylofuranosyl thiazole 4 carboxamide a new Tiazofurin analogue with potent antitumour activity
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Mirjana Popsavin, Miloš Svirčev, Gordana Bogdanovic, Vesna Kojic, Sasa Spaic, Velimir PopsavinAbstract:Abstract A new Tiazofurin analogue, 2-(3-amino-3-deoxy-β- d -xylofuranosyl)thiazole-4-carboxamide ( 3 ), was synthesized starting from d -glucose and evaluated for its in vitro antiproliferative activity against a panel of human tumour cell lines. Compound 3 exhibited the most powerful cytotoxicity against K562 cells, being approximately 100-fold more potent than Tiazofurin. This analogue was also active against Jurkat, HT-29 and HeLa malignant cells, with respective IC 50 values being ca. 2-, 27- and 17-fold lower than those observed for Tiazofurin. Remarkably, compound 3 did not exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cell line.
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Synthesis and Biological Activity of Some New 5′‐O‐Acyl Tiazofurin Derivatives.
ChemInform, 2006Co-Authors: Vjera Pejanovic, Ljubica Medić-mijačević, Mirjana Dacevic, Jelena Tasic, Dragana Ugljesic-kilibarda, Vesna Piperski, Mirjana Popsavin, Esmir Gunic, Velimir PopsavinAbstract:Three new 5'-O-acyl Tiazofurin derivatives 2-4 were synthesized and evaluated for their antiproliferative activity against different tumour cell lines as well as for their ability to induce apoptosis in C6 cells in vitro. Apart of the antitumour assays, the cell membrane permeation of 2-4 and their intracellular metabolism in C6 cells in vitro was also studied in order to evaluate their potential as possible Tiazofurin bioisosteres or prodrugs.
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Synthesis and Antiproliferative Activity of Two New Tiazofurin Analogues with 2′-Amido Functionalities.
ChemInform, 2006Co-Authors: Mirjana Popsavin, Miloš Svirčev, Ljilja Torović, Gordana Bogdanović, Vesna Kojić, Velimir PopsavinAbstract:Two novel Tiazofurin analogues 2 and 3 were synthesized starting from d-glucose. The key step of the synthesis was the efficient one-step hydrogen sulfide-mediated conversion of 2-azido-3-O-acyl-ribofuranosyl cyanides to the corresponding 2-amido thiocarboxamides. Compounds 2 and 3 were evaluated for their in vitro antiproliferative activity against certain human tumour cell lines. Remarkably, compound 2 was found to be 570-fold more potent than Tiazofurin against MCF-7 cells, while compound 3 showed the most powerful cytotoxicity against HT-29 cancer cells, being almost 100-fold more active than Tiazofurin.
Weining Zhen - One of the best experts on this subject based on the ideXlab platform.
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Biochemical consequences of resistance to Tiazofurin in human myelogenous leukemic K562 cells.
Cancer Research, 1993Co-Authors: Hiremagalur N. Jayaram, Weining Zhen, Kamran GharehbaghiAbstract:Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, Tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to Tiazofurin were developed by drug-selection pressure. Compared to a concentration producing 50% cell proliferation reduction that was 9.1 µm in sensitive cells, the resistant variants displayed concentrations producing 50% cell proliferation reductions of 12 and 16 mm. The activity of the target enzyme, IMP dehydrogenase, was not altered in the resistant cells. Studies on Tiazofurin metabolism revealed that resistant variants formed
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Clinical pharmacokinetic study of Tiazofurin administered as a 1-hour infusion
International journal of cancer, 1992Co-Authors: Hiremagalur N. Jayaram, Guido Tricot, Ronald Hoffman, Elizabeth Lapis, Weining Zhen, Edith Paulik, Patricia Kneebone, George P. Engeler, George WeberAbstract:Tiazofurin, 2-β-d-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with Tiazofurin with I-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 Tiazofurin peak plasma concentrations were 245, 441 and 736 μM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our I -hr infusion method, biphasic pharmacokinetics were noted with αt1/2 and βt1/2 of 0.5 and 6.2 hr, and Tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our I -hr infusion was 52% of that reported for the same dose given by continuous infusion. Our I -hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of Tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using I -hr infusion may be feasible for other carefully selected types of malignancies.
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Schedule-dependent synergistic action of Tiazofurin and dipyridamole on hepatoma 3924A cells
Cancer Chemotherapy and Pharmacology, 1992Co-Authors: Hiremagalur N. Jayaram, Weining Zhen, Konrad Pillwein, Kimie Murayama, George WeberAbstract: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 μ m , 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 LC_50 of 24 μ m and an IC_50 of 29 μ m 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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Antitumor activity of Tiazofurin in human colon carcinoma HT-29.
Cancer investigation, 1992Co-Authors: Weining Zhen, Hiremagalur N. Jayaram, George WeberAbstract:Tiazofurin is effective in treating end-stage leukemic patients (Tricot et al., Cancer Res 49:3696-3701, 1989). In sensitive tumors, the active metabolite of Tiazofurin, TAD, potently inhibits IMP dehydrogenase activity, resulting in reduced guanylate pools. To elucidate Tiazofurin activity in human solid tumors, we examined its activity in human colon carcinoma HT-29. Tiazofurin exhibited an LC50 of 35 microM in cultured HT-29 cells. Incubation of HT-29 cells with 100 microM Tiazofurin for 2 h resulted in TAD formation (9.3 nmol/g cells) and in a 64% decrease in GTP pools. For biochemical and chemotherapy studies, athymic nude mice were transplanted s.c. with HT-29 cells. Twenty-four days later, mice were injected i.p. with Tiazofurin (500 mg/kg); 6 h later, tumors were removed and analyzed. These tumors formed 17 nmol/g of TAD with decreased GTP pools (56%). To study oncolytic activity, transplanted mice were treated 24 h later with Tiazofurin (500 mg/kg, once a day for 10 days). To examine the effectiveness of Tiazofurin in established tumors, the drug was administered to mice 14 days after tumor implantation (500 mg/kg, once a day for 5 days, course repeated 4 times with a 10-day rest). Both treatment schedules resulted in significant antitumor activity. This study illustrates the potential usefulness of Tiazofurin in treating human colon carcinoma.
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Cytotoxicity of Tiazofurin and its arabinose and xylose analogues in K562 cells
Biochemical and biophysical research communications, 1991Co-Authors: Weining Zhen, Hiremagalur N. Jayaram, Barry M. Goldstein, Victor E. Marquez, David A. Cooney, George WeberAbstract:Summary 2-β-D-Arabinofuranosylthiazole-4-carboxamide and 2-β-D-xylofuranosyl-thiazole-4-carboxamide are sugar modified analogues of Tiazofurin, a C-glycosyl nucleoside which after anabolism to the dinucleotide, TAD (thiazole-4-carboxamide adenine dinucleotide), exhibits antitumor activity. However, ara-T and xylo-T did not exhibit cytotoxicity. Compared to Tiazofurin, only 12.5% of the ara-T and 8.8% of the xylo-T were metabolized to TAD derivatives by human myelogenous leukemia K562 cells. This was reflected in the finding that guanylate pools were not depressed after treatment with either Tiazofurin derivative. These results provide evidence that the ribose moiety is essential for the metabolism and cytotoxicity of Tiazofurin. This investigation should be helpful in the design of new analogues of Tiazofurin for future clinical trials.
