Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Tiazofurin-induced autosecretion of IL-6 and hemoglobin production in K562 human leukemia cells. 909 85

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) regulates the de novo synthesis of guanine ribonucleotides (GNT). IMPDH activity varies inversely with intracellular [GNT] and is linked to cellular proliferation. K562 leukemia cell growth was studied relative to IMPDH expression and activity following culture of the cells with Tiazofurin, an IMPDH inhibitor. Tiazofurin depressed IMPDH activity and [GTP] in K562 cells, and also increased IMPDH mRNA expression. Following exposure to Tiazofurin, K562 cell proliferation, entry into cycle, and sensitivity to cycle-active cytotoxic agents were increased. These findings indicate that the efficacy of standard chemotherapy in bcr-abl positive leukemias might be enhanced if combined sequentially with Tiazofurin.
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PMID:Effects of the IMP-dehydrogenase inhibitor, Tiazofurin, in bcr-abl positive acute myelogenous leukemia. Part II. In vitro studies. 1538 Mar 36


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