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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Tiazofurin action in leukemia: evidence for down-regulation of oncogenes and synergism with retinoic acid. 220 22

Epidemiologic studies have linked infection by the human T-lymphotropic virus type I (HTLV-I) with the development of adult T-cell leukemia. The low penetrance of the virus and the long latency for disease manifestation are factors that obscure the role of HTLV-I infection in oncogenesis. We have used an in vitro transformation assay system to determine directly whether the HTLV-I tax gene has transformation potential. Transfection of the tax gene alone into early-passage rat embryo fibroblasts did not induce morphological alterations. However, cotransfection of tax with the selectable marker plasmid pRSVneo gave rise to G418-resistant colonies that could be established as immortalized cell lines. Cotransfection of tax with the ras oncogene into rat embryo fibroblasts gave rise to foci of transformed cells that were highly tumorigenic in nude mice. These data represent a direct demonstration of the oncogenic potential of the tax gene in nonlymphoid cells and establish HTLV-I as a transforming virus.
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PMID:The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. 240 46

hst-1, or HSTF1 in human gene nomenclature, was originally identified as a transforming gene in DNA samples from human stomach cancer by NIH3T3 transfection assay. Many reports have followed to show the presence of a transforming hst-1 gene in various types of cancerous and noncancerous tissues, suggesting that the hst-1 gene is the most common non-ras transforming gene. We cloned the hst-1 genomic fragments from DNAs of a normal individual and a patient with leukemia and also from NIH3T3 cells themselves. All of these clones transformed NIH3T3 cells upon transfection. Sequence analysis of the cDNA and genomic hst-1 led us to conclude that the normal hst-1 protein transforms NIH3T3 cells when its expression is deregulated. The hst-1 protein has 40-50% homology to basic and acidic fibroblast growth factors (FGFs) and to the int-2 protein. The purified hst-1 protein synthesized in a baculovirus system was a potent heparin-binding growth factor for a variety of cells, including human endothelial cells. The hst-1 protein, when it was added to the culture medium, induced morphological transformation of NIH3T3 cells and anchorage-independent growth of NRK cells. The hst-1 gene is located 35 kbp downstream of one of its homologous genes, int-2, on human chromosome 11 at band q13.3. As in the case with the int-2 gene, the hst-1 transcripts were not detected in adult mice but found in mouse embryos. A relatively large amount of the hst-1 message was present in a mouse teratocarcinoma cell line, F9, while the int-2 mRNA was barely detected. Upon induction of differentiation in vitro, the hst-1 transcription was depressed to almost nil, and the int-2 message increased dramatically. The hst-1 and int-2 genes were coamplified in a variety of cancer cells, most notably in more than 50% of esophageal cancers.
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PMID:Biological significance of the hst-1 gene. 253 8

A myc-containing recombinant feline leukemia provirus, designated FTT, was molecularly cloned from the cat T-cell lymphoma line F422. Its transforming activity, as well as the nucleotide sequence of the 3' 2.7 kilobases of FTT, including v-myc, was determined. The predicted v-myc protein differs from feline c-myc by three amino acid changes and is truncated by two amino acids at the carboxyl terminus. Comparison with feline leukemia virus (FeLV), feline c-myc, and other FeLV proviruses indicates that recombination junctions involved in the generation of FeLV-onc viruses occur at preferred locations within the virus. They usually follow or occur within the sequence ACCCC at 5' junctions and may result from homologous recombination between sequences of marked purine-pyrimidine strand bias, especially at 3' junctions. Some recombination sites also resemble recombinase recognition sequences utilized in immunoglobulin and T-cell receptor variable-region joining. Transfection of primary rat embryo fibroblasts and subsequent in vivo analysis revealed that morphologic and tumorigenic transformation require cotransfection of FTT with human EJ-ras DNA; neither gene alone is sufficient. FTT v-myc is expressed in these transformed rat cells as a 3.0-kilobase subgenomic RNA; however, in contrast to the depressed level of c-myc expression in v-myc-involved feline tumors, steady-state levels of rat c-myc RNA and protein are apparently unaltered.
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PMID:Structure, origin, and transforming activity of feline leukemia virus-myc recombinant provirus FTT. 253 7

We have reported previously that the Kirsten murine sarcoma virus (Ki-MSV) that carries the v-Ki-ras oncogene prevents C3H10T 1/2 fibroblasts from being able to respond to interferon-gamma (IFN-gamma) with the expression of the class II major histocompatibility complex (MHC) antigen, H-2A. In this report we investigate further as to whether MSV or its parent virus Kirsten murine leukaemia virus (Ki-MLV) is able to reduce host class I MHC antigen expression. The results demonstrate that class I expression is diminished in MSV-infected cells over a time-course of 7 days after exposure to IFN-gamma and over a range of IFN-gamma concentrations. The optimal concentration of IFN-gamma for maximal class I expression remained unchanged. Cells infected with Ki-MLV, which failed to abolish the induction by IFN-gamma of class II antigens, also expressed lower levels of class I antigens, similar to those for cells infected with Ki-MSV, after exposure to IFN-gamma. It is likely therefore that the inhibition of class I induction is due to genetic material shared between the viruses, principally in the long terminal repeats (LTR), and hence that the mechanism of action is distinct from that responsible for the abolition of class II induction by Ki-MSV alone. Since class I antigens are required for CD8+ T cells (mainly cytotoxic T cells) to recognize (foreign) antigen this reduction in class I expression might lead to reduced visibility of infected cells to T cells and thus might contribute to the tumorigenicity of Ki-MSV-infected cells.
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PMID:Regulation of IFN-gamma-induced host cell MHC antigen expression by Kirsten MSV and MLV. I. Effects on class I antigen expression. 254 13

The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, we have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10(4) foci per microgram of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, we found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which we had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo (M. Souyri, C. F. Koehne, P. V. O'Donnel, T. H. Aldrich, M. E. Furth, and E. Fleissner, Virology 158:69-78). However, similarly poor oncogenicity was also observed when the v-H-ras coding sequence was inserted in pSV(X) vector, which indicated that the vector sequences play a crucial role in the pathogenicity of a given oncogene. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.
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PMID:Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors. 254 8

In vitro DNA amplification and synthetic oligonucleotide hybridization was used to analyze 57 acute myelocytic leukemias (AML) for the presence of ras gene mutations. We demonstrated mutated alleles in 19% of primary AMLs (10/51) as well as in five of six secondary leukemias. Mutations occurred predominantly at N-ras codons 12, 13, or 61 (13 cases) and twice at Ki-ras codons 12 and 13. Ras gene mutations were preferentially associated with an M4 morphology according to the FAB (French-American-British) classification, but no particular correlation was observed with respect to clinical parameter (sex, age, course of disease) or immunophenotype and karyotype. Mutated ras alleles were absent in nine mutation-positive cases analyzed during remission. However, a more complex pattern emerged from the five patients analyzed in relapse exhibiting identical ras mutations in three cases, absence of a mutated allele in one patient, and acquisition of a N-ras mutation in yet another case, in which no mutation had been detected initially. Moreover, restriction fragment length polymorphisms (RFLP) of the X-chromosome genes hypoxanthine phosphoribosyl transferase (HPRT) and phosphoglycerate kinase (PGK) were studied in 19 of the AML patients. Nine cases (47%) were heterozygous for BglI or BamHI RFLPs at the PGK or HPRT loci, respectively, and therefore suitable for clonal analysis investigating X-chromosome inactivation. All of the patients exhibited a monoclonal leukemic cell population at presentation. In addition, five of seven cases studied in remission showed reemergence of a polyclonal pattern. However, two children exhibited persistence of monoclonal hematopoiesis despite complete clinical/hematological remission and a corresponding loss of a mutated ras allele in one of the patients. These data indicate the value of molecular genetic approaches for evaluation of the heterogeneous nature of remission and relapse in AML.
Leukemia 1989 Apr
PMID:Acute myeloid leukemia: analysis of ras gene mutations and clonality defined by polymorphic X-linked loci. 256 52

Human continuous bone marrow cultures were established from intraoperative marrow specimens and infected with amphotropic murine leukemia virus (Am-MuLV) pseudotypes of Kirsten or Harvey murine sarcoma virus, and the biologic effects were compared with mouse continuous bone marrow cultures. Cultures were tested for production of total nonadherent granulocytes and granulocyte-macrophage progenitor cells (GM-CFUc); virus replication by supernatant reverse transcriptase activity; percentage of adherent and nonadherent cells and GM-CFUc that released virus by infectious center assay; and for synthesis of Harvey ras p21 protein. High-efficiency, stable Am-MuLV infection of over 90% of human marrow-culture nonadherent and adherent cells and both seven- and 14-day GM-CFUc were detected as Kirsten or Harvey pseudotype virus release by infectious center assay. Synthesis of Harvey ras p21 was detected in the adherent and nonadherent cell populations of human as well as mouse continuous marrow cultures infected with Kirsten or Harvey pseudotype virus. In contrast to data with mouse cultures, cumulative production of GM-CFUc and differentiated granulocytes in human cultures was not detectably altered by Harvey or Kirsten virus infection, and all cultures ceased to produce hematopoietic cells by 20 weeks. Of 54 virus-infected cultures in ten separate experiments, 13 produced a second peak of nonadherent cells (greater than 10(5) per flask) after 20 weeks, significantly more frequently than did control uninfected cultures (one of 32). When subcultured, these harvests produced permanent Epstein-Barr virus (EBV)-transformed pre-B cell lines that released the original inoculating pseudotype virus. Thus, Am-MuLV is a potentially valuable vector for inserting genetic sequences by recombinant techniques into human hematopoietic and stromal cells in culture; however, activation of EBV may be a significant complication.
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PMID:Amphotropic retrovirus vector transfer of the v-ras oncogene to human hematopoietic and stromal cells in continuous bone marrow cultures. 257 39

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) is a synthetic nucleoside inhibitor of inosine monophosphate dehydrogenase. This agent has recently been shown to induce differentiation of human leukemia cell lines. In the present study, we have monitored the effects of tiazofurin on differentiation and proto-oncogene expression in K562 erythroleukemia cells. Tiazofurin induced K562 cell hemoglobin production in a concentration-dependent manner. This induction of a differentiated phenotype was also associated with a loss of proliferative capacity. In contrast to the reversible effects of hemin on induction of K562 cell hemoglobin synthesis, the effects of tiazofurin were irreversible. Northern blot analysis of K562 cells treated with 10 microM tiazofurin demonstrated the accumulation of alpha- and gamma-globin mRNA. The results also demonstrate that there was little if any effect of tiazofurin on levels of c-myc, c-myb, or c-abl mRNA. Furthermore, there were no detectable changes in Ki-ras, Ha-ras or N-ras expression at the mRNA and protein levels in tiazofurin-treated K562 cells. These findings suggest that tiazofurin induces changes in levels of globin transcripts but has little if any effect on c-myc, c-myb, c-abl, or c-ras gene expression in K562 cells.
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PMID:Effects of tiazofurin on globin and proto-oncogene expression in K562 erythroleukemia cells. 263 29

Point mutations within codon 12 of the Harvey (H-) ras proto-oncogene have recently been implicated in the progression of hemopoietic malignancy, particularly chronic myeloid leukemia. We have analyzed DNA from 170 cases of acute and chronic leukemia by using a restriction fragment length polymorphism. No evidence for clonal allelic H-ras codon 12 activation was found among these cases, which included 23 cases of chronic myeloid leukemia, 12 of which were in accelerated phase or blastic transformation. These data suggest that H-ras codon 12 mutations occur infrequently in hemopoietic neoplasms generally and may be less important in disease progression than has been previously suggested.
Leukemia 1989 Jan
PMID:Activation of Harvey ras oncogene by mutation at codon 12 is very rare in hemopoietic malignancies. 264 80


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