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Biomedical subjects

M L Sherman

Publications and source records attributed to M L Sherman.

At least 73 records · Page 4Linked to original sources
PubMed1989

Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans.

Several investigators have reported that tumor necrosis factor (TNF) can alter the hemostatic properties of vascular endothelial cells in vitro. We have examined the in vivo effects on the hemostatic mechanism of recombinant human TNF administered as a continuous intravenous infusion to 23 cancer patients with active disease. A battery of sensitive and specific immunochemical techniques were used to monitor changes in blood coagulability. Serial determinations of F1 + 2, the protein C activation peptide (PCP), and fibrinopeptide A (FPA) were obtained prior to the initiation of the TNF infusions and at three and 24 hours after the start of therapy in 12 individuals who received greater than 3 x 10(5) U/m2/24h. The mean levels of F1 + 2, PCP, and FPA were significantly elevated at both time points as compared to the baseline values. The metabolic behavior of 125I-F1 + 2 in an animal model was not affected by infusions of the cytokine. We therefore conclude that the observed elevations in the concentration of this marker in humans receiving TNF result from hemostatic system hyperactivity. In 11 subjects infused with 1 x 10(5) to 2.4 x 10(5) U/m2/24 h of the cytokine, the mean levels of F1 + 2, PCP, and FPA were not significantly greater at 24 hours as compared with the baseline values, indicating that there is a threshold dose at which the cytokine can exert a biochemical effect on the coagulation system. Our studies demonstrate that TNF is able to provide a substantial net procoagulant stimulus to the hemostatic mechanism, and suggest that this cytokine may be a mediator of certain hypercoagulable states in humans.

Blood Coagulation Tests↗
PubMed1989

Tiazofurin induction of mouse erythroleukemia cell hemoglobin production in the absence of commitment or changes in protooncogene expression.

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), is a synthetic nucleoside inhibitor of inosine monophosphate dehydrogenase and blocks guanine nucleotide biosynthesis. In the present study, we examined the effects of tiazofurin on mouse erythroleukemia (MEL) cell differentiation and protooncogene expression. Tiazofurin induced hemoglobin production in MEL cells in a concentration-dependent manner, as measured by an increase in benzidine staining. Northern blot analysis of MEL cells treated with 7 mumol/L tiazofurin demonstrated accumulation of both alpha- and beta-globin RNA transcripts. This induction of differentiation was blocked by the presence of exogenous guanosine (100 mumol/L). In contrast to the down-regulation of c-myc and c-myb RNA in MEL cells induced by dimethyl sulfoxide (DMSO) or hexamethylene bisacetamide (HMBA), there was no detectable change in levels of these transcripts after tiazofurin treatment. Furthermore, MEL cells induced by tiazofurin did not commit to terminal differentiation. These results suggest a role for guanine nucleotides, at least in part, in the regulation of MEL cell differentiation.

Animals↗
PubMed1988

CSF-1 and C-FMS gene expression in human carcinoma cell lines.

The macrophage-specific colony stimulating factor CSF-1 is required for the growth and differentiation of monocytes. The cell surface receptor for CSF-1 is identical to the product of the c-fms proto-oncogene. The present studies have monitored CSF-1 and c-fms expression in human carcinoma cell lines. Two of three human ovarian carcinoma cell-lines expressed multiple species of CSF-1 mRNA. Furthermore, detection of CSF-1 transcripts was associated with secretion of CSF-1 protein that was increased after phorbol ester treatment. CSF-1 mRNA was also detectable in 4 breast and 2 lung carcinoma cell lines. In contrast, c-fms expression was found only in SK-Br-3 breast carcinoma cells. Similar studies in 2 human choriocarcinoma cell lines demonstrated the presence of c-fms, but not CSF-1, transcripts. While phorbol ester treatment was associated with increased c-fms mRNA levels in choriocarcinoma cells, this agent had no effect on CSF-1 expression. These findings indicate that: 1) CSF-1 expression is frequent in human ovarian, breast and lung carcinoma cells; and 2) coexpression of the CSF-1 and c-fms genes, as found in monocytes is infrequent in malignant epithelial and choriocarcinoma cell lines.

Blotting, Northern↗
PubMed1988

Effects of tiazofurin on protooncogene expression during HL-60 cell differentiation.

The synthetic nucleoside analogue, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) is an inhibitor of the enzyme inosine monophosphate (IMP) dehydrogenase and depletes guanine nucleotide pools. In the present study, we have monitored the effects of tiazofurin on human HL-60 promyelocytic cell differentiation and protooncogene expression. Tiazofurin (10 microM) induced a more differentiated HL-60 cell phenotype as determined by histochemical staining and decreased myeloperoxidase gene expression. This induction of differentiation was associated with a loss of proliferative capacity and decreases in clonogenic survival. The results also demonstrate that tiazofurin induces a down-regulation of c-myc mRNA levels. In contrast, there was no detectable change in the level of 3.8-kilobase c-myb transcripts. Furthermore, treatment of HL-60 cells with tiazofurin resulted in the appearance of an additional c-myb mRNA with an apparent size of 3.3 kilobases. The addition of guanosine to tiazofurin-treated HL-60 cells prevented the down-regulation of c-myc transcripts and also inhibited induction of the 3.3-kilobase c-myb transcript. Moreover, this additional transcript was not detected during induction of HL-60 cells by dimethyl sulfoxide, tumor necrosis factor, and retinal, but was induced by another IMP dehydrogenase inhibitor, mycophenolic acid. These results suggest a role for guanosine ribonucleotides in the regulation of c-myc and c-myb gene expression during HL-60 cell differentiation. The results also suggest that changes in c-myb expression can be dissociated from that of c-myc and induction of myeloid differentiation.

Cell Differentiation↗
PubMed1988

Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.

Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Adolescent↗
PubMed1988

Effect of tumor necrosis factor on GTP binding and GTPase activity in HL-60 and L929 cells.

Tumor necrosis factor (TNF) is a monokine that induces pleiotropic events in both transformed and normal cells. These effects are initiated by the binding of TNF to high affinity cell surface receptors. The post-receptor events and signaling mechanisms induced by TNF, however, have remained unknown. The present studies demonstrate the presence of a single class of high affinity receptors on membranes prepared from HL-60 promyelocytic leukemic cells. The interaction of TNF with these membrane receptors was associated with a 3.8-fold increase in specific binding of the GTP analogue, GTP gamma S. Scatchard analysis of GTP gamma S binding data demonstrated that TNF stimulates GTP binding by increasing the affinity of available sites. The TNF-induced stimulation of GTP binding was also associated with an increase in GTPase activity. Moreover, the increase in GTPase activity induced by TNF was sensitive to pertussis toxin. The results also demonstrate that TNF similarly increased GTP binding and pertussis toxin-sensitive GTPase activity in membranes from mouse L929 fibroblasts, thus indicating that these effects are not limited to hematopoietic cells. Analysis of HL-60 membranes after treatment with pertussis toxin in the presence of [32P]NAD revealed three substrates with relative molecular masses of approximately Mr 41,000, 40,000, and 30,000. In contrast, L929 cell membranes had only two detectable pertussis toxin substrates of approximately Mr 41,000 and 40,000. Although the Mr 41,000 pertussis toxin substrate represents the guanine nucleotide-binding inhibitory protein Gi, the identities of the Mr 40,000 and Mr 30,000 substrates remain unclear. In any event, inhibition of the TNF-induced increase in GTPase activity and ADP-ribosylation of Gi by pertussis toxin suggested that TNF might act by increasing GTPase activity of the Gi protein. However, the results further indicate that TNF has no detectable effect on basal or prostaglandin E2-stimulated cAMP levels in HL-60 cells. Taken together, these findings indicate that a pertussis toxin-sensitive GTP-binding protein other than Gi, and possibly the Mr 40,000 substrate, is involved in the action of TNF. Finally, the demonstration that pertussis toxin inhibited TNF-induced cytotoxicity in L929 cells supports the presence of a GTP-binding protein which couples TNF-induced signaling to a biologic effect.

Adenosine Diphosphate Ribose↗
PubMed1988

Modulation of cyclic AMP levels and differentiation by adenosine analogs in mouse erythroleukemia cells.

Friend virus-transformed mouse erythroleukemia (MEL) cells can be induced to undergo erythroid differentiation by a variety of compounds, including dimethyl sulfoxide (DMSO) and the adenosine analog xylosyladenine. The present studies have monitored the effects of the stable adenosine receptor ligand N6-phenylisopropyladenosine (PIA) on induction of MEL cell differentiation. PIA has been previously shown to stimulate adenylate cyclase activity in rat hepatic and mouse Leydig 1-10 cells as well as inhibit adenylate cyclase in adipocytes. In the present study, PIA was ineffective as an inducer of the differentiated MEL cell phenotype. However, the results demonstrate that PIA inhibits the induction of MEL cell differentiation by DMSO and xylosyladenine. The extent of this inhibition as determined by benzidine staining, induction of globin RNA, and loss of self-renewal capacity was dependent on PIA concentration. The results also demonstrate that PIA induces a rapid and sustained increase in cyclic AMP (cAMP) levels. Furthermore, there was a highly significant correlation between cAMP levels and inhibition of xylosyladenine-induced differentiation (r = 0.962, P less than 0.0005). This relationship is further supported by the demonstration that prostaglandins E1 and E2 increase MEL cell cAMP levels and inhibit induction of the differentiated MEL cell phenotype. Moreover, PIA inhibited induction of MEL cell differentiation by butyric acid, diazepam, hypoxanthine, and the aminonucleoside analog of puromycin. These results suggest that cAMP may act as a negative regulatory signal in the induction of MEL cell differentiation.

Adenosine↗
PubMed1988

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

Chemical and Drug Induced Liver Injury↗
PubMed1988

Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.

After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.

Acute-Phase Proteins↗
PubMed1987

Clinical studies with tumour necrosis factor.

The mechanism of tumour necrosis factor (TNF) cytotoxicity remains unknown. The in vivo antitumour effects of TNF may be related to direct cytotoxicity, immunomodulatory effects or endothelial effects on tumour vasculature. Phase I and early Phase II clinical trials of human recombinant TNF are under way in Japan, the USA, the UK and Germany. The maximum Phase II dose for TNF has not been established. The clinical toxicity of TNF is generally similar to that of other biological agents. Systemic toxicity, including fever, chills, anorexia and nausea, has been seen in most patients treated with TNF and has not been clearly related to dose. Other toxicities have included liver function abnormalities, hypotension, transient neurological changes and haematological abnormalities. Few clinical responses have been reported but organized Phase II testing remains to be completed. Combination trials with interferons have recently been initiated. Phase II efficacy studies of TNF as a single agent and in combination are needed for an assessment of the value of this agent in cancer therapy.

Chemical and Drug Induced Liver Injury↗
PubMed1987

Nifedipine is an antagonist to cyclotron resonance enhancement of 45Ca incorporation in human lymphocytes.

The incorporation of 45Ca in mixed human lymphocytes was measured following one-hour exposures of the cells to combined steady and periodic magnetic fields designed to probe for cyclotron resonance response in calcium incorporation. Measurements were made as a function of magnetic field frequency, up to 30 Hz, and as a function of magnetic field amplitude, up to 1.5 x 10(-4) Trms. The amplitude measurements demonstrated that the relative 45Ca uptake at resonance follows different mechanisms of interaction above and below 0.2 x 10(-4) Trms. After adjusting the magnetic field configuration for maximum incorporation, we then determined the effects of the calcium influx blocker nifedipine on 45Ca incorporation, with and without simultaneous exposure to this specific magnetic field combination. The presence of nifedipine in both unexposed and exposed cell suspensions resulted in decreased 45Ca uptake, presumably through the slow inward calcium channels. Evidence was found suggesting that nifedipine acts antagonistically to the 45Ca cyclotron resonance tuning signal.

Calcium↗
PubMed1986

Inhibitory effects of theophylline and dibutyryl cAMP on murine erythroleukemia cell differentiation.

Murine erythroleukemia cells can be induced to differentiate by a variety of compounds. We have previously shown that 5'-methylthioadenosine, an inhibitor of cAMP phosphodiesterase, blocks induction of these cells. The present study demonstrates that theophylline, another cAMP phosphodiesterase inhibitor, also blocks murine erythroleukemia cell differentiation in a concentration-dependent manner. Northern blot analysis indicates that this agent inhibits accumulation of alpha- and beta-globin transcripts. These findings are extended by demonstrating that dibutyryl cAMP exerts similar effects. Furthermore, theophylline and dibutyryl cAMP are synergistic in inhibiting appearance of the mature erythroid phenotype. The results thus suggest that cAMP regulates induction of murine erythroleukemia cell differentiation.

Animals↗
PubMed1985

Inhibition of murine erythroleukemia cell differentiation by 3-deazaadenosine.

Recent studies have demonstrated that 5'-methylthioadenosine, an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, blocks induction of murine erythroleukemia cell (MEL) differentiation. The nucleoside analogue 3-deazaadenosine (c3Ado) is both an efficient substrate and a potent inhibitor of AdoHcy hydrolase. The present study was undertaken to determine whether c3Ado would similarly inhibit MEL differentiation. The results demonstrate that c3Ado inhibits induction of MEL differentiation by dimethyl sulfoxide, hexamethylene bisacetamide, butyric acid, and diazapam. c3Ado blocks the appearance of the differentiated MEL phenotype by inhibiting both MEL heme synthesis and transcription of alpha- and beta-globin RNA. The inhibitory effect of c3Ado on MEL differentiation is concentration dependent, reversible, and potentiated by L-homocysteine thiolactone. Furthermore the AdoHcy/AdoMet ratio increases nearly 3.5-fold after 24 h of treatment with 50 microM c3Ado. In contrast, this c3Ado effect is not associated with polyamine depletion or cytostasis. These findings indicate that c3Ado blocks the induction of MEL differentiation at a transcriptional level and that this effect may be related to inhibition of AdoHcy hydrolase.

Adenosine↗
PubMed1984

Effect of 5'-methylthioadenosine on induction of murine erythroleukemia cell differentiation.

The polyamines putrescine, spermidine and spermine have been implicated in the regulation of proliferation and differentiation. The present study has monitored the effects of 5'-methylthioadenosine, the metabolic product of spermidine and spermine synthesis, on the appearance of a differentiated murine erythroleukemia cell phenotype. The results demonstrate that increasing concentrations of 5'-methylthioadenosine (1 X 10(-6) to 5 X 10(-4)M) progressively inhibit murine erythroleukemia cell heme synthesis and hemoglobin production. The results also demonstrate that this inhibition of differentiation is not related to depletion of intracellular spermidine or cytostasis. Since 5'-methylthioadenosine is also a known inhibitor of DNA methylation, this naturally occurring nucleoside may be an intermediate involved in both murine erythroleukemia cell proliferation and differentiation.

Adenosine↗