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)

Genetic changes found in human osteogenic sarcoma cells, including loss of the p53 and Rb tumor suppressor elements and overexpression of the cyclin G1 (CYCG1) proto-oncogene, suggest the potential of gene transfer as a treatment for metastatic disease. In this study, we examined the effects of antisense cyclin G1, in comparison with antisense cyclin D1 (CYCD1) and enforced expression of the universal cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the proliferation of human MG-63 osteosarcoma cells. Retroviral vectors bearing antisense CYCG1 as well as antisense CYCD1 and WAF1/CIP1 (in sense orientation) driven by the Moloney murine leukemia virus long terminal repeat promoter inhibited the growth and/or survival of transduced MG-63 cells in 2-7 day cultures. This represents the first demonstration that cyclin G1 is essential for the survival and/or growth of human osteosarcoma cells. Cytostatic and cytopathic effects were accompanied by a significant increase in the incidence of apoptosis, as determined by immunocytochemical analysis of DNA fragmentation. Furthermore, transduction of MG-63 cells with a retroviral vector bearing the suicide gene, herpes simplex thymidine kinase (HStk), induced cell death on treatment with ganciclovir, exhibiting pronounced bystander effects. Taken together, the data affirm the feasibility of modulating inducible cell cycle control enzymes as a potential gene therapy approach in the clinical management of osteogenic sarcoma.
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PMID:Retroviral vector-mediated gene transfer of antisense cyclin G1 (CYCG1) inhibits proliferation of human osteogenic sarcoma cells. 758 20

Harringtonine (HT) and homoharringtonine (HHT) are two alkaloids isolated from the bark of the evergreen tree Cephalotaxus hainanensis Li in the 1970s. They were found to have activity against murine leukemia, Lewis lung carcinoma and B16 melanoma, and used as anti-leukemia drugs clinically. Apoptosis is an active process of programmed cell suicide and now is believed to be an important target for tumor chemotherapy. In this report, the apoptosis inducing effect of HT and HHT in HL-60 cells were observed. The experiments demonstrated that 2 x 10(-7) mol.L-1 of HT and 10(-7) mol.L-1 of HHT could induce apoptosis in HL-60 cells when the cells were exposed to HT and HHT for 4 h. In agarose gel electrophoresis, DNA extracted from HL-60 cells treated with HT and HHT showed a typical internucleosomal DNA degradation, i.e., DNA ladder and parallel morphological changes as nuclear chromosome segmentation and condensation as well as cytoplasma vacuolation. This effect of HT and HHT was shown to appear in a concentration- and time-dependent manner. The efficacy of HT and HHT in inducing apoptosis of HL-60 cells was found to parallel with their cytotoxic activity in HL-60 cells. These results suggest that the mechanism of antitumor action of HT and HHT is related to their apoptosis inducing activity.
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PMID:[Induction of apoptosis by harringtonine and homoharringtonine in HL-60 cells]. 790 May 38

Allogeneic bone marrow transplantation (BMT) is associated with a severe complication--graft-versus-host disease (GVHD). Although effectively preventing GVHD, ex vivo T-lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect. The ex vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells could allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GVHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GVHD. To obtain T cells specifically depleted by GCV, we transduced primary T cells with a retroviral vector containing the HS-tk and neomycin resistance (NeoR) genes. Gene transfer was performed by coculturing PHA +/- CD3- or alloantigen-stimulated purified T cells on an irradiated retroviral vector producer cell line or by incubating the T cells in supernatant from the producer. Subsequent culture in G418 for 1 week allowed for the selection of transduced cells. GCV treatment of interleukin-2-responding transduced and selected cells resulted in greater than 80% growth inhibition, whereas GCV treatment of control cells had no effect. Similarly, the allogeneic reactivity of HS-tk-transduced cells was specifically inhibited by GCV. Combining transduced and nontransduced T cells did not show a bystander effect, thus implying that all of the cells inhibited by GCV were indeed transduced. Lastly, studies involving the transduction of the HUT-78 (T-lymphoma) cell line suggest that stable expression of HS-tk can be maintained over 3 months in vitro in the absence of G418. In summary, we have established the feasibility of generating HS-tk-transduced T cells for subsequent in vivo transfer with hematopoietic stem cells and, if GVHD occurs, specific in vivo GCV-induced T-cell depletion in allogeneic BMT recipients.
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PMID:Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation? 804 49

The mortality profile of female nurses and teachers in British Columbia (BC) was examined using age-standardized proportional mortality ratios (PMRs) calculated for the period 1950-1984. Lowered overall mortality among nurses was seen for degenerative heart disease and for cerebrovascular accidents. Significantly elevated PMR values were observed for cancer of the breast and ovary in nurses of age 20-65 years. PMRs were significantly elevated for cancer of the pancreas and leukemia among those age 20 years and older. Elevated values were also observed for motor vehicle accidents and suicide among nurses in both age groups. Lower than expected mortality from degenerative heart disease and cerebrovascular accidents was seen in working age teachers (age 20-65 years). However, elevated PMRs were detected for carcinoma of the colon, breast, endometrium, brain, and melanoma. Among those 20 years and over, significantly elevated PMRs were also observed for cancers of the ovary and other digestive organs. Elevated PMRs were found for motor vehicle and aircraft accidents. Mortality from cirrhosis of the liver was lower than anticipated in both teachers and nurses. A number of significant PMRs declined when deaths of "homemakers" were withdrawn from the comparison group used to generate PMR values, suggesting that risk of death from various causes among women working outside the home differ from those seen in women who are predominantly in the home.
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PMID:Mortality among female registered nurses and school teachers in British Columbia. 807 20

Macrophage inflammatory protein-alpha (MIP-1 alpha), an 8-kDa peptide produced by stimulated macrophages, has been recently sequenced and cloned. In addition to its inflammatory effects, MIP-1 alpha inhibits proliferation of immature hematopoietic progenitors both in vitro and in vivo. Because the gene coding for MIP-1 alpha is expressed in peripheral blood cells obtained from patients with acute myelogenous leukemia (AML), we sought to evaluate the effect of MIP-1 alpha on AML precursors. We studied bone marrow samples from 21 AML patients using both the AML blast colony assay and the delta suspension culture assay. We found that recombinant human (rh) MIP-1 alpha significantly inhibits early and mature AML progenitors with sample-to-sample variability, by up to 79% at concentrations ranging from 40 to 1600 ng/ml. These results were obtained in the presence of fetal calf serum either alone or with granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or interleukin-3. In contrast, rhMIP-1 alpha (400 ng/ml) did not significantly affect normal colony-forming unit granulocyte-macrophage (CFU-GM), or burst-forming unit-erythroid (BFU-E) proliferation. These data prompted us to delineate the inhibitory mechanism of MIP-1 alpha. Consequently, we used the thymidine suicide technique to measure DNA synthesis in AML progenitors and the enzyme-linked immunosorbent assay to quantify intracellular levels of interleukin-1 beta in AML blasts following incubation with MIP-1 alpha. We found that whereas MIP-1 alpha prevented AML progenitors from entering the proliferative phase of the cell cycle, it had no effect on interleukin-1 beta levels. Taken together, our data suggest that MIP-1 alpha may have clinical benefits in therapy for AML and should be considered for evaluation in a clinical setting.
Leukemia 1994 May
PMID:Inhibition of acute myelogenous leukemia progenitor proliferation by macrophage inflammatory protein 1-alpha. 818 37

One of the factors regulating the population size of a clone of proliferating cells is the induction of a physiological suicide mechanism known as apoptosis. We studied apoptosis in the HL-60 human promyelocytic leukemia cell line which differentiates when exposed to phorbol ester (S-cell), and in the PET-cell mutant of HL-60 which is defective in its response to phorbol ester. Exposing S-cells to 12-O-tetradecanoylphorbol 13-acetate (TPA) (3 nM and above) induced morphological changes characteristic of apoptosis (visualized by light microscopy), and induced fragmentation of chromatin DNA to oligonucleosomal lengths. These changes were obvious in 48 h. In contrast, 1000 nM TPA for five days did not induce apoptosis in the PET-cell. DNA fragmentation was induced in both cell lines by A23187 (0.25 microM) and etoposide (7 microM). Novobiocin (600 and 900 microM) induced DNA fragmentation in S-cells, but higher concentrations inhibited fragmentation. Novobiocin is believed to induce DNA fragmentation by a direct action on DNA. In the case of PET-cells, novobiocin did not induce DNA fragmentation at any concentration, and prior treatment of PET-cells with novobiocin (300-1200 microM for 30 min) inhibited DNA fragmentation induced by A23187. Novobiocin inhibited cell growth equally in S-cell and PET-cells. It is concluded that the promyelocytes have the capacity to undergo apoptosis in response to agents which activate protein kinase C, and that the PET-cell has a mutation which disables both protein-kinase C-induced and novobiocin-induced DNA fragmentation, leaving intact the ability of novobiocin to protect DNA from calcium-entry-initiated fragmentation. The elucidation of the lesion responsible for the PET phenotype is likely to increase our understanding of this important pathway for regulating cellular proliferation and how it bears on leukemogenesis and chemotherapy.
Leukemia 1993 Nov
PMID:Phorbol ester induces apoptosis in HL-60 promyelocytic leukemia cells but not in HL-60 PET mutant. 823 Dec 52

Polyamines play major roles in ionic and osmotic regulation, but their exact involvement in specific ion transport processes is poorly defined. Treatment of L1210 mouse leukaemia cells with either 5 mM alpha-difluoromethylornithine (DFMO), a suicide substrate of ornithine decarboxylase, or 25 microM N1,N12-bis(ethyl)spermine (BE-3-4-3), a dysfunctional polyamine analogue, caused a stable decreased in intracellular pH (pHi) by 0.1-0.4 unit from steady-state control values between 7.4 and 7.6, as measured either by partition of a weak acid or with a fluorescent pH-sensitive probe. This effect was not related to cell growth status or differences in metabolic acid generation, and was observed in either the presence or absence of HCO3-. Exogenous spermidine (10-25 microM) or putrescine (25-50 microM) fully reversed DFMO- or BE-3-4-3-induced acidification within 2 and 8 h respectively. Recovery of pHi in L1210 cells after a nigericin- or NH4(+)-mediated acid load in HCO3(-)-free buffers was mediated by Na+/H+ antiporter activity, in addition to a minor Na(+)-independent and amiloride-insensitive pathway. Decreased steady-state pHi was maintained in polyamine-depleted L1210 cells after recovery from acid stress. Moreover, the pHi-dependence of the rate of Na(+)-dependent H+ extrusion after an acid stress was altered by DFMO and BE-3-4-3, resulting in a set-point which was lower by 0.25-0.30 pH unit in polyamine-depleted cells. On the other hand, neither the rate nor the magnitude of Na+/H(+)-exchanger-mediated alkalinization induced by hypertonic shock was decreased by polyamine depletion. Thus polyamine depletion induces a persistent defect in pHi homeostasis which is due, at least in part, to a stable decrease in the pHi set-point of the Na+/H+ exchanger.
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PMID:Stable intracellular acidification upon polyamine depletion induced by alpha-difluoromethylornithine or N1,N12-bis(ethyl)spermine in L1210 leukaemia cells. 855 15

Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.
Leukemia 1996 May
PMID:Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors. 865 68

Allogenic hematopoietic stem cell transplantation is associated with a severe complication induced by the T-cells present in the graft: graft-vs-host disease (GVHD). While effectively preventing GVHD, ex vivo T-lymphocyte depletion of the graft unfortunately increases graft rejection and reduces the graft-vs-leukemia (GVL) effect. The ex vivo transfer to the herpes simplex thymidine kinase (HS-tk) suicide gene into T-cells before their infusion with the hematopoietic stem cells should allow for selective in vivo depletion of these T-cells with ganciclovir (GCV) if subsequent GVHD was to occur. In patients not experiencing GVHD, and therefore at a higher risk of relapse, one could preserve the beneficial effects of the donor T-cells on tumor control. Lastly, the early presence of donor T-cells in all patients should contribute to successful engraftment. We have demonstrated that retroviral-mediated transfer of HS-tk and Neomycine resistance genes in T-lymphocytes, followed by G418 selection, results in T-cells specifically inhibited by GCV with no bystander effect. In a phase I study, escalating amounts of HS-tk expressing T-cells will be infused in conjunction with a T-cell depleted marrow graft to allogenic HLA identical recipients. Toxicity, survival, alloreactivity and GCV-sensitivity of the gene-modified cells will be monitored. If successful, such an approach could significantly contribute to expanding the use of alloreactivity as a treatment modality.
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PMID:Gene transfer applied to the modulation of alloreactivity. 893 11

The epidemiologic study covered causes and levels of mortality in the settlement situated near electric power supply line (voltage is 500 kV). The work used retrospective cohort method adjusted for evaluation of mortality in general population. The study revealed no higher mortality risk with all the causes totally and with leading causal groups under influence of high frequency electromagnetic fields. However, higher relative mortality risk with leukemia and suicide appeared statistically insignificant.
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PMID:[Mortality of people residing near electric power supply line with voltage of 500 kV]. 901 27


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