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J Nafziger

Publications and source records attributed to J Nafziger.

At least 19 recordsLinked to original sources
PubMed2001

Role of iron in tumor cell protection from the pro-apoptotic effect of nitric oxide.

F2The host defense against tumor cells is in part based upon the production of nitric oxide (NO) by activated macrophages. However, carcinogenesis may involve mechanisms that protect tumor cells from NO-mediated apoptosis. In the present study, we have assessed the effects of exogenous NO on the proliferation and survival of human liver (AKN-1), lung (A549), skin (HaCat), and pancreatic (Capan-2) tumor cell lines, compared with normal skin-derived epithelial cell cultures. Except to the HaCat cell line, all of the other human epithelioid cells were sensitive to the antiproliferation effect of S-nitroso-N-acetyl-penicillamine or Deta NONOate, whereas tumor cells had low if any response to sodium nitroprusside. Growth inhibition with exogenous NO correlated with increased apoptosis, but was not mediated by cyclic GMP, peroxynitrite generation, or poly(ADP-ribose) polymerase modulation, all of which involved in NO-mediated growth inhibition of normal skin-derived epithelial cell cultures. The simultaneous addition of iron-containing compounds protected tumor cells from NO-mediated growth inhibition and apoptosis. Intracellular iron quantification indicated that, as deferoxamine, exogenous NO significantly decreased intracellular ferric iron levels in tumor cells. Together, the current study reveals that intracellular iron elevation rescues tumor cells from NO-mediated iron depletion and subsequent growth inhibition and apoptosis.

Apoptosis↗
PubMed2000

Absence of the effects of 50 Hz magnetic fields on the progression of acute myeloid leukaemia in rats.

PURPOSE: As the most recent epidemiological studies provide no definite conclusions about the effects of 50/60 Hz magnetic fields (MFs) on the incidence of leukaemia in humans, animal models in a well-controlled environment are useful for evaluating the possibility of an association between MFs and leukaemia. The present study was designed to determine whether 50 Hz magnetic fields can alter the progression of leukaemia. MATERIALS AND METHODS: A well-characterized model of transplantable acute myeloid leukaemia in rats was used for the first time. This model is closely related to human acute myeloid leukaemia, the type most frequently reported in epidemiological studies of adults. After leukaemic cell implantation, rats were exposed to a sinusoidal 50 Hz MF of 100 microT for 18 h a day, 7 days a week, throughout leukaemia progression. The parameters investigated were: survival time, body weight, haematologic parameters, infiltration of blood, bone marrow, spleen and liver by leukaemic cells. RESULTS: The results showed no significant changes (p > 0.05) in leukaemic MF-exposed versus unexposed rats for any of the parameters involved in leukaemia progression. CONCLUSION: These data do not support the hypothesis that 50 Hz magnetic fields influence leukaemia progression in humans.

Adult↗
PubMed2000

Can 50 Hz magnetic fields alter iron metabolism and induce anaemia?

UNLABELLED: PURPOSE. Some changes in tissue iron concentration have been reported in animals exposed to electromagnetic fields. In other studies, variations in the haemoglobin level were occasionally observed. In the present experiment, the effects of exposing a rat to a 50 Hz magnetic field (MF) were therefore investigated for the possible induction of anaemia due to changes in iron metabolism. MATERIALS AND METHODS: Male Brown Norway rats (n=225) were exposed to a sinusoidal 50 Hz MF of 500 microT for 15 weeks. Haematological parameters, differential bone marrow cell counts and sideroblasts were investigated. Blood parameters of iron metabolism were measured. Iron concentration and total iron content were also determined in the spleen and liver, to assess iron storage in these organs. RESULTS: Significant differences between the exposed and control rat were only detected for iron storage in the spleen, and for the percentage of bone marrow cells of the red cell lineage. CONCLUSION: The changes observed were not associated with anaemia during the 15 weeks of MF exposure. However, the decrease in bone marrow cells of the red cell lineage and the changes in iron storage detected at the end of the experiment did not allow the possibility to be ruled out that exposure to 50 Hz MFs may induced delayed biological effects.

Anemia↗
PubMed1999

Early steps of replication of moloney murine leukemia virus in resting lymphocytes.

We explored the role of cell type in the early steps of replication of Moloney murine leukemia virus (Mo-MLV) by comparing viral entry and reverse transcription in physiologically quiescent peripheral blood B and T lymphocytes. Virus entry was identical in both cell types. In contrast to previous results, full-length viral DNA was synthesized in resting B lymphocytes, but in agreement with earlier reports, reverse transcription was abortive in resting T lymphocytes. The addition of exogenous nucleosides in the culture medium of resting T lymphocytes allowed reverse transcription to proceed in these cells, without inducing cell cycling. These data suggest that the difference in the ability of quiescent T and B lymphocytes to sustain reverse transcription of Mo-MLV can be explained by a difference in the dNTP pool sizes of these two populations of quiescent cells.

Animals↗
PubMed1998

A new anthracycline with potent anti-leukemic activity overcomes P-glycoprotein multidrug resistance.

In this study, we assessed the ability of a new anthracycline, moflomycin, to circumvent multidrug resistance. Moflomycin showed superior anti-proliferative activity compared to daunorubicin and doxorubicin on two resistant cell lines: leukemic HL-60 cell line resistant to daunorubicin (HL-60/DR) and breast cancerous cell line resistant to doxorubicin (MCF-7/AR). The effect of moflomycin on cell proliferation was correlated with an increased uptake and a decreased cellular efflux. The data obtained in the presence of the P-gp inhibitor, verapamil, confirmed the absence of interaction between P-gp and moflomycin. Our results indicate that moflomycin exhibits an important reduction in cross-resistance with daunorubicin and doxorubicin resulting from its ability to circumvent P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Synthesis, DNA-binding properties and cytotoxic activity of flavin-oligopyrrolecarboxamide and flavin-oligoimidazolecarboxamide conjugates.

The aim of this study was to develop novel series of photosensitizer-DNA minor groove binder hybrids composed of a flavin (isoalloxazine) chromophore linked to a moiety related to netropsin or distamycin. Three series (Fla-Pyr, Fla-Gly-Pyr and Fla-Gly-Im) were synthesized which differ by the number and the nature of the heterocyclic nuclei in the oligopeptide units, the nature of the linker and its anchoring position on the flavin. In terms of DNA binding and DNA specificity, satisfactory data are obtained in the Fla-Pyr and Fla-Gly-Pyr series; in terms of photo-induced cytotoxicity, the results are disappointing. The present study allows us to draw the following structure-activity relationships: (i) substitution of the flavin nucleus in either the N3 or the N10 position does not affect the activity; (ii) tris-pyrrolic hybrids are more efficient than bis- and tetra-pyrrolic analogs; (iii) the presence of a glycin in the linking chain does not suppress the DNA binding properties or the cytotoxic activities of the hybrids; and (iv) the replacement of the pyrrole nuclei by imidazoles has a drastic effect since it results in the loss of DNA affinity and cytotoxicity.

Aminoimidazole Carboxamide↗
PubMed1997

Investigation of the effects of 50 Hz magnetic fields on purified human hematopoietic progenitors.

Epidemiological reports suggest a possible association between exposure to extremely low frequency electromagnetic fields (ELF-EMFs) and the frequency of leukemia in men working in the field of electricity or in children living near power lines. At present, there is no experimental evidence for such an association. In this study we investigated the effects of 50 Hz EMFs (sinusoidal EMF of 10 microT or 1 mT) on human purified hematopoietic progenitor cells which are the first targets of a leukemogenic process. The results failed to reveal any significant changes in cell proliferation, cell kinetics, ultrastructure or clonogenic potential of these progenitors which could be related to a leukemogenic effect.

Aged↗
PubMed1997

Factors involved in the anaemia of chronic disorders in elderly patients.

Erythropoietin secretion was evaluated in the anaemia of chronic disorders in elderly patients, since it has been shown that this secretion is impaired in adults. We looked for a possible role of inflammatory cytokines: tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) on erythropoietin production. The influence of nutritional status on the anaemia was also investigated. Erythropoietin secretion was significantly increased in elderly patients with anaemia of chronic disorders (ACD) and inversely correlated with haemoglobin concentrations in infectious and inflammatory diseases. Plasma TNF alpha levels were significantly enhanced only in cancerous patients, but no correlation could be established between TNF alpha and erythropoietin or haemoglobin. No noticeable increase of IL-1 beta levels was observed in ACD. These findings suggest that systemic TNF alpha or IL-1 beta are not involved in the erythropoietin response to ACD. Albumin levels were decreased in anaemic patients. Further investigations of the effects of a nutritional supplementation in elderly patients with ACD may be of interest.

Aged↗
PubMed1996

Enhanced topoisomerase II-induced DNA breaks and free radical production by a new anthracycline with potent antileukemic activity.

In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.

Antibiotics, Antineoplastic↗
PubMed1995

Effects of 50 Hz magnetic fields on C-myc transcript levels in nonsynchronized and synchronized human cells.

The effects of 50 Hz electromagnetic fields (EMFs) on the expression of the c-myc oncogene, known to be involved in normal cell proliferation and possibly also in tumor processes, were investigated in nonsynchronized human lymphoid cells immortalized by Epstein-Barr virus. Viral injury to such cells makes them a good model for exploring the possible cancer-promoting effects of 50 Hz magnetic fields. Parallel experiments were conducted on human HL60 leukemic cells. Cells were exposed to sinusoidal 50 Hz EMFs at 10 microT or 1 mT for 20 min, 1 h, 24 h, or 72 h. Exposure was performed either immediately after refeeding or 1.5 h after refeeding. C-myc transcript values were assessed by Northern blot analysis and normalized to those of the noninducible gene GaPDH. No statistically significant difference between the c-myc transcript levels of control and exposed cells was found in lymphoid or leukemic cells under our experimental conditions, either after short exposures of 20 min and 1 h or after longer exposures of 24 and 72 h. Other experiments were carried out with pseudosynchronized cells in an attempt to establish whether cells were especially sensitive to 50 Hz magnetic field exposure in any particular phase of the cell cycle. Accordingly, cells were pseudosynchronized in G0/G1 by serum deprivation and exposed for 20 min to a 50 Hz magnetic field, at 10 microT for lymphoid cells and 1 mT for HL60 cells. No significant difference was observed between the c-myc transcript levels of control and exposed cells for either of the synchronized cell types. These results for synchronized cells correlated with those for nonsynchronized cells.

Blotting, Northern↗
PubMed1995

A new anthracycline with potent antileukemic activity exhibits reduced mutagenicity.

The mutagenicity of a new anthracycline (moflomycin) with potent antileukemic activity was studied by the Ames test in four strains of Salmonella typhimurium (TA97a, TA98, TA100 and TA102), and compared to the mutagenicity of doxorubicin, widely used as antineoplastic agent. Unlike doxorubicin, moflomycin displayed no mutagenic activity in strains TA98 and TA100. Low mutagenicity was only observed in TA102 strain and was not enhanced after metabolic activation. This result indicates that moflomycin induce mutagenicity by reverting base-pair substitution. The structural changes in the sugar moiety may be involved in the reduced mutagenicity of moflomycin. The low mutagenicity of moflomycin shown in this study enhances the potential advantage of this new derivative which displays a high antileukemic activity.

Antibiotics, Antineoplastic↗
PubMed1995

[Comparison of the effects of ketorolac and aspirin on hemostasis in the rabbit].

OBJECTIVE: Comparison of ketorolac with aspirin and placebo for the antithrombotic activity using the Folts' model of experimental arterial thrombosis and the perioperative blood loss. STUDY DESIGN: Experimental randomized blinded study anaesthetized, tracheotomized and mechanically ventilated. Carotid blood flow variations were detected by a probe directly inserted around the artery and monitored by an electromagnetic flowmeter. A segment of the exposed carotid artery was de-endothelialized by gently squeezing the artery with a needle holder forceps, and an external constrictor was placed around it (stenosis 60%), to induce cyclic flow reductions (CFR). During 20 min, CFR rate was assessed. Animals were then randomized in 3 groups of 9: ketorolac (K) 1 mg.kg-1, aspirin (A) 10 mg.kg-1 or saline (S), injected intravenously (peripheral ear vein). After drug administration, CFR rate was assessed over 20 min, to determine the potential antithrombotic activity of the drug (curative phase). Thereafter, the opposite carotid artery was injured and stenosed and the occurrence of CFR was assessed over 20 min (preventive phase). The amount of blood loss of a xipho-pubic laparotomy with a spleen section was also measured 30 min after drug administration. RESULTS: In all untreated animals, CFRs developed with a mean rate of 4 cycles/20 min. Aspirin completely abolished CFR during the curative phase in all rabbits, except in one. No effect was observed during this phase with ketorolac or saline. During the preventive phase, a partial inhibition of CFRs was induced by ketorolac and aspirin. Peri-operative bleeding was not increased significantly by ketorolac or aspirin. Postinjection bleeding-time did not differ between the three groups. CONCLUSIONS: Ketorolac (1mg.kg-1) has not a strong antithrombotic activity. Ketorolac and aspirin do not increase peri-operative blood loss, and therefore do not seem to strongly interfere with haemostasis in the rabbit.

Animals↗
PubMed1993

Decreased erythropoietin responsiveness to iron deficiency anemia in the elderly.

The prevalence of anemia in the elderly raises the question of an inappropriate secretion of erythropoietin in response to increased demands. Therefore, the serum erythropoietin concentration of elderly patients (74-95 years) with iron deficiency anemia was measured and compared to that of iron deficiency anemic adults (25-60 years). A lowered erythropoietin secretion in response to anemia was observed in elderly patients in comparison with adults. However, the serum erythropoietin of the anemic elderly was inversely correlated with hemoglobin levels as shown for the anemic adults. The progressive reduction of the renal function observed with aging could explain the decreased capacity of erythropoietin secretion in elderly patients.

Adult↗
PubMed1991

Inhibitory effect of new imidazole derivatives on the proliferation and nucleic acid synthesis of leukemic cells.

New derivatives of imidazothiazole and imidazobenzothiazole were tested in vitro for their potential antiproliferative activity. Four imidazobenzothiazole derivatives exhibited a cytotoxic activity against two leukemic cell lines, compound I being the most effective. Cell cycle kinetics studies showed that this drug delays the progression of cells from G1 to S and G2 M phases. An inhibitory effect on DNA and RNA synthesis was also observed. The antiproliferative effect of this compound, analogue of immunosuppressive agents, suggested that it could be of interest for a therapeutic use and for the synthesis of new derivatives.

Cell Cycle↗
PubMed1991

Pharmacological and physicochemical properties of a new anthracycline with potent antileukemic activity.

The antiproliferative effect of F860191, a new anthracycline with high antitumor activity in L1210 leukemia-inoculated mice, was investigated in vitro on different leukemia cell lines. Comparison of the IC50 value of F860191 with that of daunorubicin and doxorubicin disclosed a superior activity for this drug against the three leukemia cell lines tested. Studies on the mechanism of the antiproliferative activity showed that F860191 induced a G2 + M arrest in the cycle of treated cells. Physicochemical properties of this drug suggested that the high cytotoxic effect of F860191 could be related to its capacity to induce free radicals and to generate DNA breaks through its interaction with topoisomerase II.

Animals↗
PubMed1990

Specific high-affinity receptors for interferon-gamma on mouse bone marrow-derived mast cells: inhibitory effect of interferon-gamma on mast cell precursors.

Cultured mast cells derived from murine bone marrow were investigated for the presence of specific interferon-gamma (IFN-gamma) receptors, and for the effects of IFN-gamma on mast cell proliferation. 125I-labeled recombinant IFN-gamma (125I-Mu-rIFN-gamma) was shown to bind to high-affinity receptors on these cells. Scatchard analysis of binding data indicated the presence of about 500 homogeneous binding sites per cell, with an apparent equilibrium dissociation constant of 3 X 10(-10) M. The binding of 125I-Mu-rIFN-gamma to mast cells was inhibited by unlabeled Mu-rIFN-gamma but not by unlabeled Mu-IFN-alpha/beta. Cross-linking of 125I-Mu-rIFN-gamma to mast cell membrane proteins using a cross-linking agent yielded a predominant complex of 100 +/- 10 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography which most likely represents the IFN-gamma-receptor complex. To assess the biological significance of these receptors, we studied the effects of Mu-rIFN-gamma on mast cell proliferation, which was markedly inhibited in mast cell precursors but not in mature mast cells. These in vitro results are in agreement with the antiproliferative effect of IFN-gamma previously reported for other hematopoietic progenitors, and suggest that IFN-gamma could find its application in the treatment of human systemic mastocytosis.

Animals↗
PubMed1988

[Effect of retinoic acid on the differentiation and growth of murine mastocyte precursors].

In cultures of normal mouse hematopoietic cells containing Interleukin-3 develop cells with many features of mast cells. These cells seem heterogeneous with respect to morphological and biochemical examination. Nevertheless, most of the cells show many granules and a low ability to self-renew. In the present report we describe the development of a blastic cell population, termed mastoblasts, when normal mouse hematopoietic cells are exposed continuously to retinoic acid (RA: 10(-6) to 10(-5) M/l). Using H*3-thymidine incorporation, cell cycle measurement and protein content by flow cytometry, transmission and scanning electron microscopy, we show that these cells seem to be of mast cell lineage but with a high self-renewing capability. So, RA is able to inhibit mast cell differentiation and to provide us a "mastoblastic" population which could be used as a model to study mast cell differentiation.

Animals↗