Tiazofurin action in leukemia: evidence for down-regulation of oncogenes and synergism with retinoic acid.

  title={Tiazofurin action in leukemia: evidence for down-regulation of oncogenes and synergism with retinoic acid.},
  author={George Weber and Yasufumi Yamaji and M Nagai and Yutaka Natsumeda and Hiremagalur N. Jayaram and Weining Zhen and E. Paulik},
  journal={Advances in enzyme regulation},
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… Expand
8 Citations
Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity.
  • J. Ban, G. Weber
  • Biology, Medicine
  • Biochemical and biophysical research communications
  • 1992
Tiazofurin and DFDC are synergistically cytotoxic in hepatoma cells and additive in PANC-1 cells and should be helpful in treating leukemias and solid tumors in humans. Expand
Expression of memory to the terminal differentiation inducing activity of tiazofurin in HL-60 leukemia cells.
The finding that memory was blocked when primed cells were exposed to cycloheximide during the intervening inducer-free interval, but not during the priming or subsequent drug exposure periods has significance with respect to the sequence of events required for commitment to a differentiation pathway. Expand
Regulation of de novo and salvage pathways in chemotherapy.
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. Expand
Retinoid therapy of childhood cancer.
Although early studies sought to overcome the pharmacologic limitations of ATRA therapy in APL, the demonstration that ATO is active against APL in RA-refractory patients has led to a focus on studies employing ATO. Expand
Anti‐tumor activity of mycophenolate mofetil against human and mouse tumors in vivo
Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti‐tumor activity of the potent IMPExpand
Regulation of GTP biosynthesis.
In support of enzyme-pattern-targeted chemotherapy, evidence was provided for synergistic chemotherapy with tiazofurin (inhibitor of IMPDH) and hypoxanthine (competitive inhibitor of GPRT and guanine salvage activity) in patients and in tissue culture cell lines. Expand
Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates
The biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyClic linkers, or to prodrug moieties are reviewed. Expand


Clinical and molecular impact of inhibition of IMP dehydrogenase activity by tiazofurin.
Evidence was provided for the role of IMP dehydrogenase and guanylates in the expression of the neoplastic program in cancer cells with particular relevance to human leukemic cells and the possible relevance to clinical treatment that tiazofurin might also act through down-regulation of ras oncogene. Expand
Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.
Tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational,Biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy. Expand
Hematological and biochemical action of tiazofurin (NSC 286193) in a case of refractory acute myeloid leukemia.
Tiazofurin appears to be a promising agent in the treatment of leukemia because of its selective action on leukemic cells and the availability of a rapid in vitro method capable of predicting sensitivity of leukeMic cells to the agent and monitoring its activity during treatment by measuring thiazole-4-carboxamide adenine dinucleotide and GTP concentrations. Expand
Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukemia.
Bone marrow aspirates and peripheral blood samples showed that with tiazofurin treatment there was an induced differentiation of the myelocytes, and 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 tiaz ofurin. Expand
IMP dehydrogenase: inhibition by the anti-leukemic drug, tiazofurin.
The affinity of TAD to leukemic IMP dehydrogenase was three orders of magnitude higher than the natural product NADH, which contribute to an understanding of the mechanism of action of tiazofurin in the treatment of leukemia. Expand
Synergistic action of tiazofurin and retinoic acid on differentiation and colony formation of HL-60 leukemia cells.
Tiazofurin and retinoic acid synergistically induced differentiation and inhibited colony formation in HL-60 human promyelocytic leukemia cells in cell culture. The synergism was the result ofExpand
Initial studies on the mechanism of action of a new oncolytic thiazole nucleoside, 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193).
The drug was producing a state of guanine deprivation was provided by high performance liquid chromatography analysis of acid-soluble extracts: a time-dependent fall in the concentrations of GMP and GTP ensued upon exposure to the drug; on the other hand, IMP concentrations increased by ∼15-fold. Expand
Down-regulation of c-myc and c-Ha-ras gene expression by tiazofurin in rat hepatoma cells.
Evidence is provided in support of the earlier demonstrated correlation in K562 cells between GTP concentration and expression of c-myc and c-ras genes that might depend on GTP for their expression in hepatoma cells and they might cooperate in a signal pathway that controls cell proliferation. Expand
Cellular oncogenes and multistep carcinogenesis.
Two dozen cellular proto-oncogenes have been discovered to date through the study of retroviruses and the use of gene transfer, and recent work provides experimental strategies by which many of them, as well as oncogene of DNA tumor viruses, may be placed into functional categories. Expand
Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Memorial Lecture.
  • G. Weber
  • Philosophy, Medicine
  • Cancer research
  • 1983
L'essence et the substance des progres theoriques and experimentaux vers une connaissance de la strategie biochimique et de the logique de l'expression des genes dans les cellules cancereuses et on identifie un programme enzymatique et metabolique commun dansles diverses tumeurs animales and humaines. Expand