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Biomedical subjects

D R Spriggs

Publications and source records attributed to D R Spriggs.

At least 55 records · Page 3Linked to original sources
PubMed1990

A phase I study of intermittent continuous infusion high dose cytosine arabinoside for acute leukemia.

We previously administered ara-C at a dose rate of 250 mg/m2/hr for 36-72 hr to patients with leukemia. Gastrointestinal toxicity was dose-limiting. This regimen was modified to an every other day schedule, administering 24-hr periods of high dose continuous infusion ara-C, each followed by a 24-hr rest period. Sixteen patients with relapsed/refractory acute myeloid leukemia (AML) (N = 4), secondary AML (N = 2), relapsed/refractory acute lymphoblastic leukemia (N = 7), or CML in blast crisis (N = 3) received this regimen of three 24-hr infusions with two intercurrent 24-hr rest periods. Grade 3 gastrointestinal toxicity was encountered in 57% of the courses, and hypoplasia was achieved in all patients. Three of the patients died while hypoplastic, two with septicemia and another with intracranial hemorrhage. There were five responding patients (2 CRs, 3 PRs). Median steady-state plasma ara-C levels were 24 microM, 22 microM, and 20 microM during the first, second, and third 24-hr infusions, respectively. Ara-C levels ranged from 4-118 microM during the infusions and were always below 4.5 microM during the rest periods. A significant level of ara-C incorporation into DNA was detected in each of the five patients studied, thus demonstrating that (ara-C)DNA formation is detectable in blasts from patients receiving high dose continuous infusion ara-C therapy. These findings suggest that alternate day continuous infusion ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.

Adult↗
PubMed1989

Circulating interleukin 6 during a continuous infusion of tumor necrosis factor and interferon gamma.

Plasma samples obtained from patients receiving a 24-h continuous infusion of human recombinant (hr)TNF or a combination of two overlapping, 24-h continuous infusions of hrIFN-gamma and hrTNF were analyzed for IL-6 in a sensitive bioassay. A transient appearance of circulating IL-6 was observed with peak levels between 3 and 6 h after the start of the hrTNF infusion. These peak levels correlated quite well with the dose of hrTNF administered (r = 0.86; p less than 0.001). The maximal value observed was 27.5 ng/ml IL-6 in a sample of a patient receiving 545 micrograms/m2 hrTNF. The combination of hrIFN-gamma (200 micrograms/m2) and hrTNF in the infusions resulted in higher IL-6 levels than a comparable dose of hrTNF alone. A maximal value of 23.5 ng/ml IL-6 was observed in a patient receiving 205 micrograms/m2 hrTNF. No IL-6 was found in the plasma of patients during the 12-h infusion with hrIFN-gamma alone, except for two borderline samples.

Drug Administration Schedule↗
PubMed1989

Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation.

We report that tumor necrosis factor alpha (TNF-alpha) mRNA is increased after treatment with x-rays in certain human sarcoma cells. An increase in TNF-alpha mRNA is accompanied by the increased production of TNF-alpha protein. TNF-alpha enhances radiation lethality in both TNF-alpha-producing and -nonproducing tumor cells. These data suggest that, in addition to the direct cytotoxic effects of x-rays, production of TNF-alpha may add to radiation lethality through autocrine and paracrine mechanisms. Combinations of TNF-alpha and therapeutic radiation may be useful in clinical cancer therapy.

Cell Line↗
PubMed1989

Chronic TNF infusion causes anorexia but not accelerated nitrogen loss.

It has been proposed that many of the physiologic and metabolic changes that occur during critical illness and malignancy are mediated by the cytokine tumor necrosis factor alpha/cachectin (TNF). To test this hypothesis, a study of the metabolic responses that occurred during 5 days of continuous intravenous (I.V.) infusion of TNF both in rats and tumor-bearing humans was conducted. TNF administration was associated with anorexia, fluid retention, acute phase responses, and negative nitrogen balance. In both species, changes in nitrogen balance were related to the onset of anorexia and not to the development of hypermetabolism and accelerated net tissue breakdown. TNF may represent the primary afferent stimulus inducing many of the metabolic changes that occur during critical illness, but it is not solely responsible for the accelerated net proteolysis that occurs in these patients.

Acute Disease↗
PubMed1989

A phase I trial of recombinant human tumor necrosis factor and interferon-gamma: effects of combination cytokine administration in vivo.

The combination of tumor necrosis factor (TNF) and interferon-gamma has synergistic bioactivity in numerous preclinical model systems. We have tested this potential synergism in vivo by administration of both cytokines to patients with advanced cancer using overlapping 24-hour continuous intravenous (IV) infusions in a phase I trial. Thirty-six patients were treated with a fixed dose of interferon-gamma (200 micrograms/m2/d) with interpatient dose escalation of TNF (from 5 to 205 micrograms/m2/d). The dose-limiting toxicity at the maximal-tolerated dose (MTD) of TNF (205 micrograms/m2) with interferon-gamma was hypotension. Other toxicities noted included an influenza-like syndrome, transient decreases in circulating leukocyte and platelet counts, subclinical evidence of disseminated intravascular coagulation, and the sporadic occurrence of acute pulmonary toxicity. The recommended phase II dose for this combination schedule is TNF, 136 micrograms/m2, with interferon-gamma, 200 micrograms/m2. The addition of interferon-gamma to TNF resulted in a greater than three-fold increase in toxicity compared with TNF administered as a single agent, supporting the hypothesis that the combination of these cytokines may induce synergistic effects in vivo.

Adult↗
PubMed1989

Effects of tiazofurin on globin and proto-oncogene expression in K562 erythroleukemia cells.

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.

Actins↗
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↗
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

Detection of circulating tumor necrosis factor after endotoxin administration.

Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1 beta, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240 +/- 70 pg per milliliter, as compared with 35 +/- 5 pg per milliliter after saline administration. Host responses were temporally associated with the increase in circulating tumor necrosis factor at 90 minutes, and the extent of symptoms, changes in white-cell count, and production of ACTH were temporally related to the peak concentration of tumor necrosis factor. Ibuprofen pretreatment did not prevent the rise in circulating tumor necrosis factor (mean peak plasma level, 170 +/- 70 pg per milliliter) but greatly attenuated the symptoms and other responses after endotoxin administration. Concentrations of circulating interleukin-1 beta and gamma interferon did not change after endotoxin administration. We conclude that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.

Adrenocorticotropic Hormone↗
PubMed1988

Interleukin-2 initiates metabolic responses associated with critical illness in humans.

The cytokine interleukin-2 is a primary modulator of the immune response that occurs after infection, trauma, and transplant rejection, yet its role as a mediator of associated metabolic changes in surgical illness is unknown. We studied clinical and metabolic responses in eleven tumor-bearing humans with normal renal and hepatic function receiving bolus intravenous (I.V.) interleukin-2 (30,000 U/kg). Additional subjects (n = 6) were pretreated with the cyclooxygenase inhibitor, ibuprofen (1600 mg, orally), before interleukin-2 administration. Serial measurements were made of vital signs, symptoms, hematology, and plasma concentrations of pituitary and stress hormones and selected cytokines. Administration of interleukin-2 resulted in fever, tachyacardia, "flu-like" symptoms, and neurohormonal elaboration. The responses observed were quantitatively similar to those that occurred after endotoxin administration in healthy subjects (n = 13), but differed in the following manner: 1) the onset of fever and endocrine changes occurred after a longer latent interval (180-240 minutes vs. 60-90 minutes after endotoxin), 2) peak responses after the administration of interleukin-2 also occurred later, 3) no increased circulating tumor necrosis factor was detected after administration of interleukin-2 (peak plasma concentration was greater than 35 pg/ml vs. 270 +/- 70 pg/ml after endotoxin administration), and 4) administration of interleukin-2 but not of endotoxin was associated with increased circulating concentrations of gamma interferon (peak plasma concentration 1.7 +/- 0.2 NIH U/ml vs. less than 0.1 NIH U/ml after endotoxin administration). Fever and neurohormonal responses after interleukin-2 administration were greatly attenuated by ibuprofen administration. Interleukin-2 induces other cytokines that exert their effects largely through the cyclooxygenase pathway. Interleukin-2 may be an important signal, initiating the integrated host responses to infection and injury.

Adrenocorticotropic Hormone↗
PubMed1988

Tumor necrosis factor expression in human epithelial tumor cell lines.

Tumor necrosis factor (TNF) is a monokine with in vitro cytotoxicity for some but not all tumor cells. The basis for sensitivity and resistance to the antitumor effects of this agent remains unclear. The present studies have monitored the effects of TNF on 14 epithelial tumor cell lines. Eleven of these cell lines were resistant to the growth inhibitory effects of TNF (50% inhibitory concentration greater than 1,000 U/ml). 12 of the 14 tumor cell lines has detectable levels of high affinity cell surface TNF binding sites, thus suggesting that resistance was not often due to the absence of cell surface TNF receptors. Northern blot analysis demonstrated that three of the eleven resistant cell lines expressed detectable levels of TNF mRNA. Furthermore, both sensitive and resistant epithelial tumor cells had the capacity to express TNF transcripts in the presence of the protein synthesis inhibitor, cycloheximide. Finally, the presence of TNF expression at the RNA level is shown to be associated with the production of a TNF-like protein in the resistant Ov-D ovarian carcinoma cells. These findings suggest that certain human epithelial tumor cell lines inherently resistant to TNF also express this cytokine.

Animals↗
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↗
PubMed1988

Phospholipase C activates protein kinase C and induces monocytic differentiation of HL-60 cells.

Phospholipase C (PLC)-mediated hydrolysis of membrane phospholipids results in the production of diacylglycerol, inositol phosphates, and choline metabolites. Inositol triphosphate increases calcium levels, while diacylglycerol activates protein kinase C. The present studies demonstrate that exogenous PLC generates inositol phosphates, releases choline metabolites, and activates protein kinase C in human HL-60 promyelocytic leukemia cells. PLC also induced monocytic differentiation of HL-60 cells as manifested by adherence, growth inhibition, and appearance of monocytic cell surface antigens. Furthermore, PLC treatment decreased c-myc mRNA levels and induced c-fos, c-fms, and tumor necrosis factor transcripts. The changes in gene expression induced by PLC are similar to those previously shown to be associated with phorbol ester-induced monocytic differentiation of HL-60 cells. Our results thus demonstrate that exogenous PLC activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation. PLC may therefore play a role in transducing signals from physiological inducers of monocytic differentiation.

Cell Differentiation↗
PubMed1988

Prolonged high dose ARA-C infusions in acute leukemia.

High doses of cytosine arabinoside (ara-C) were administered by continuous infusion to 24 patients with acute leukemia in relapse or blast phase of chronic myelogenous leukemia (CML). Ara-C was infused at a dose rate of 250 mg/M2/hr for 36 to 72 hr. The major toxicities were myelosuppression, diarrhea, and abdominal pain. Other toxicities included pulmonary edema, neurotoxicity, and liver function abnormalities. The gastrointestinal toxicity was dose-limiting and a phase II dose was established at 250 mg/M2/hr for 60-72 hr. Four patients treated with this dose schedule had objective responses. Two patients with CML in blast phase returned to chronic phase and have remained stable without maintenance therapy for 12 and 18 months. Two patients with acute myelogenous leukemia in relapse entered complete remissions which continued unmaintained for 4 and 6 months. Steady-state plasma ara-C levels ranged between 7 and 24 x 10(-6) M, while ara-U levels were as high as 4.5 x 10(-4) M. There was no detectable accumulation of ara-C or ara-U during the infusion period. These findings would suggest that the continuous infusion of high dose ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.

Adult↗
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↗