Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returned to the range of untreated animals. The decrease of IMP DH activity (t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1/2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0, 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
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PMID:Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. 790 99

Conventional antileukemic chemotherapy in relapsed or refractory acute leukemia or myeloid blast crisis of chronic granulocytic leukemia (CGL) is not curative and remissions, if attained, are usually of short duration. The primary goal of antileukemic therapy in these patients should be the identification of agents that are more selective and better targeted in their action. Tiazofurin is known to inhibit inosine 5'-phosphate dehydrogenase (IMPDH), the rate limiting enzyme of de novo guanine ribonucleotide synthesis. The activity of this enzyme is markedly increased in leukemic cells. To prevent de novo GTP synthesis, it is also necessary to block the guanine-salvaging activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This was achieved by increasing the plasma levels of hypoxanthine through the administration of allopurinol. Twenty-seven patients with end stage leukemia or myeloid blast crisis of CGL were treated with tiazofurin. Assays of IMPDH activity and GTP concentrations in leukemic cells, as well as hypoxanthine levels in the serum, provided a method to monitor the impact of tiazofurin/allopurinol therapy and to adjust drug doses. In these poor prognosis patients seven attained a complete response (CR), 3 had a hematologic improvement and an antileukemic effect was seen in 4. An excellent correlation was observed between biochemical and clinical activity of tiazofurin/allopurinol, with biochemical responses preceding clinical results. However, clinical responses were usually short-lived with IMPDH activity starting to increase soon after discontinuation of therapy, but patients responding again after reinstitution. Tiazofurin therapy was generally well tolerated in patients with less than 15 days of treatment and no other major medical complications. Although an antiproliferative effect was observed in some patients, bone marrows remained cellular in most cases with a marked shift from blasts to granulocytes. Severe neutropenia was absent in the majority of cases and patients could be discharged in good clinical condition immediately after completion of therapy. Tiazofurin/allopurinol therapy provided a rational, biochemically targeted and biochemically monitored approach to the treatment of poor prognosis leukemia and should serve as a paradigm in enzyme pattern-targeted chemotherapy.
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PMID:Biochemically targeted therapy of refractory leukemia and myeloid blast crisis of chronic granulocytic leukemia with Tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity. 904 9

Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.
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PMID:Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis. 904 10

Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, selenazofurin, and benzamide riboside share similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.
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PMID:Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis. 1039 Jun 1

The effect of Tiazofurin (TR) on the in vitro growth of bone marrow (BM) and peripheral blood (PB) leukemic progenitors was investigated in 29 patients. Nineteen of the patients were suffering the blast crisis of chronic myeloid leukemia (bcCML) and ten patients refractory acute myeloid leukemia (AML). PB and BM mononuclear cells were cultured in methylcellulose alone or with concentrations of TR ranging between 10 and 200 microM. TR produced a dose dependent inhibition of colony forming unit (CFU)-blast growth in all the samples tested from BM and PB. The most effective concentrations of TR used were 150 and 200 microM, while concentrations of less than 50 microM TR were not adequate for 50% inhibition of cell growth (IC50). Differences were found in the response of CFU-blasts to TR related to the type of underlying leukemia. Inhibition of CFU-blast growth was more pronounced in bcCML than in AML in both the BM and PB samples. The concentration of TR required to induce IC50 in bcCML was 50 microM, while the same effect in AML required a concentration of 150 microM. Analysis of the control samples also revealed that CFU-blasts from bcCML produced smaller numbers of colonies, though these differences were not statistically significant. It has therefore been demonstrated that TR has strong in vitro anti-leukemic activity, more pronounced in bcCML than in refractory AML. We thus feel this study gives further rationale for the clinical application of TR, and would strongly support this.
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PMID:In vitro sensitivity of hematopoietic progenitors to tiazofurin in refractory acute myeloid leukemia and in the blast crisis of chronic myeloid leukemia. 1276 23

Six patients with bcr-abl positive AML or chronic myelogenous leukemia in blast crisis (CML-BC) were treated with the IMP-dehydrogenase (IMPDH) inhibitor, Tiazofurin, in a Phase-II trial. Tiazofurin was given by IV infusion (2200-2700 mg/m2 per day) for up to 10 days. Leukemia blasts rapidly disappeared from the circulation of patients during treatment, while mature myeloid cells in the marrow increased in number. Although these hematologic responses were transient, persisting less than 3-4 weeks, our findings confirm that Tiazofurin has anti-leukemia activity. This drug warrants further study in combination regimens with other chemotherapeutic agents for the treatment of bcr-abl positive AML and CML-BC.
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PMID:Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part I. In vivo studies. 1538 Mar 35

Inosine 5'-monophosphate dehydrogenase (IMPDH) represents an attractive target for the development of anticancer agents; however, there are no drugs aimed at this target for the treatment of cancer currently available on the market. Tiazofurin, a potent IMPDH inhibitor, reached clinical trials with Orphan Drug status for the treatment of patients in blast crisis of chronic myelogenous leukemia (CML); however, it was considered too toxic for application against other malignancies and no development has been reported for this drug since 2002. Formulations of mycophenolic acid, another potent inhibitor of IMPDH, are currently used for the prevention of rejection following transplantation, and against autoimmune diseases. More recently, numerous studies have demonstrated the potential of mycophenolic acid as an anticancer agent, with a phase I clinical trial in patients with advanced multiple myeloma ongoing. Furthermore, synergy between imantinib and mycophenolic acid in CML treatments has also been reported. Related compounds such as mycophenolic adenine dinucleotides, along with second-generation analogs, are undergoing preclinical evaluation, while another inhibitor of IMPDH, AVN-944, is currently in phase I clinical trials to investigate the treatment of hematological malignancies. This article reviews recent applications of IMPDH inhibitors as anticancer agents, and highlights the progress that has been made in this field.
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PMID:Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. 1765 81


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