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Biomedical subjects

D R Spriggs

Publications and source records attributed to D R Spriggs.

At least 73 records · Page 4Linked to original sources
PubMed1987

Human granulocyte-macrophage colony-stimulating factor induces expression of the tumor necrosis factor gene by the U937 cell line and by normal human monocytes.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts profound effects on the proliferation, differentiation, and effector function of myeloid lineage cells. In contrast to its growth-promoting effects on normal myeloid progenitor cells, we found that GM-CSF unexpectedly inhibited the colony growth of U937 cells in agar culture. Furthermore, medium conditioned by recombinant GM-CSF(rGM-CSF)-treated U937 cells was found to exert an inhibitory effect on subsequent U937 colony growth that was partially due to the presence of tumor necrosis factor (TNF). By Northern blot analysis, rGM-CSF was shown to induce expression of the TNF gene in U937 cells and in T-lymphocyte-depleted, monocyte-enriched peripheral blood mononuclear cells. Furthermore, rGM-CSF was observed to significantly enhance TNF secretion by monocytes stimulated with endotoxin and phorbol myristate acetate (PMA). These data suggest that some of the biological effects of GM-CSF may be amplified through the release of monokines such as TNF.

Cell Line↗
PubMed1986

Effects of cis-diamminedichloroplatinum on DNA incorporation and cytotoxicity of 1-beta-D-arabinofuranosylcytosine.

1-beta-D-Arabinofuranosylcytosine (ara-C) incorporates into replicating cellular DNA and the extent of this incorporation correlates with loss of clonogenic survival. More recent findings have demonstrated that incorporation of ara-C into DNA undergoing repair of damage induced by u.v. light also results in cell lethality. On the basis of previous studies demonstrating a marked synergism between cis-diamminedichloroplatinum (CDDP) and ara-C in LoVo colon carcinoma cells, the present work has examined the interaction of these agents at a biochemical and cellular level in the MCF-7 human breast carcinoma line. The extent of ara-C incorporation into MCF-7 DNA correlated significantly with loss of clonogenic survival in a dose-dependent manner. The effects of CDDP on the formation of MCF-7 (ara-C)DNA were monitored using both cesium sulfate and cesium chloride density centrifugation. The results demonstrate that CDDP had little, if any, detectable effect on incorporation of ara-C into DNA. Furthermore, combinations of CDDP and low concentrations of ara-C (10(-7) and 10(-6) M) decreased MCF-7 clonogenic survival in an additive but not synergistic manner. Modest synergy was detectable with CDDP and higher ara-C concentrations (10(-5) and 10(-4) M). The interaction between CDDP and ara-C was apparently dependent on concentration, duration of exposure and cell type. There was no dramatic synergy between CDDP and ara-C in MCF-7 cells. These findings may be relevant to the design and interpretation of CDDP/ara-C clinical trials.

Breast Neoplasms↗
PubMed1986

Low dose ara-C administered by continuous subcutaneous infusion: a pharmacologic evaluation.

Low dose ara-C has been widely used in the treatment of preleukemia and leukemia. These studies have generally utilized either a twice daily, subcutaneous bolus schedule or a continuous intravenous infusion schedule. In order to surmount the logistical problems of long term intravenous infusion while providing prolonged ara-C exposure, we have studied the pharmacology of administering ara-C (20 mg/M2/d) by continuous subcutaneous infusion. The results obtained in eight patients demonstrate that steady state plasma ara-C levels achieved during continuous subcutaneous infusion (24.6-65.6 nM) are not significantly different than those obtained during intravenous infusions (26.2-61.5 nM). Subcutaneous infusions result in prolonged myelosuppression similar to that seen with continuous intravenous infusions. The continuous infusion of low dose ara-C by the subcutaneous route provides a treatment option for some outpatients and offers advantages over intravenous infusions which often require placement of venous catheters or hospitalization.

Adult↗
PubMed1986

Genetic basis for altered pathogenesis of an immune-selected antigenic variant of reovirus type 3 (Dearing).

In this paper we provide a step by step comparison of the pathogenesis of murine infection caused by reovirus type 3 (Dearing) and an antigenic variant (K) selected by its resistance to neutralization with a monoclonal antibody (G5) directed against the T3 hemagglutinin. To show that specific changes in the biologic properties of variant K were due to mutation in the S1 double-stranded RNA segment (gene), which encodes the viral hemagglutinin, we generated a reassortant virus ("1 HA K") containing the variant K S1 gene and compared its properties to variant K and to a reassortant ("1 HA 3") containing the T3 (Dearing) S1 gene. These studies, in conjunction with our previous nucleotide sequence analysis of the S1 genes of variant K and T3 (Dearing) [R. Bassel-Duby, A. Jayasuriya, D. Chatterjee, N. Sonenberg, J. V. Maizel, Jr., and B. N. Fields, Nature (London) 315:421-423, 1985; R. Bassel-Duby, D. R. Spriggs, K. L. Tyler, and B. N. Fields, submitted for publication], indicate that a single amino acid change in the T3 hemagglutinin can alter viral growth and tropism within the central nervous system without affecting either its primary replication in the intestine or its pattern of spread to or within the central nervous system.

Animals↗
PubMed1986

Identification of attenuating mutations on the reovirus type 3 S1 double-stranded RNA segment with a rapid sequencing technique.

Reovirus type 3 variants with mutations in the major neutralization domain of the sigma 1 protein have attenuated neurovirulence and restricted neurotropism. We devised a variation of the rapid RNA sequencing technique to facilitate the analysis of double-stranded RNA. We sequenced the S1 double-stranded RNA segment, which encodes the sigma 1 protein, of five attenuated reovirus type 3 variants. Four of the variants have changes in codon 419, and a fifth variant has a change at codon 340, all of which resulted in amino acid substitutions in the sigma 1 protein. We identified two sites on the reovirus type 3 sigma 1 protein that play a critical role in neurovirulence.

Amino Acid Sequence↗
PubMed1986

Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study.

Fludarabine phosphate (NSC 312878), an adenosine deaminase resistant analogue of 9-beta-D-arabinofuranosyladenine, has entered clinical trials. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform myelosuppression, as well as occasional nausea, vomiting, and hepatotoxicity. Three episodes of metabolic acidosis and lactic acidemia were noted. In addition, three patients suffered neurotoxicity. Two of these three patients had a severe neurotoxicity syndrome characterized by blindness, encephalopathy, and coma. Neither patient recovered neurological function. Neuropathological findings at autopsy were characterized by a diffuse, necrotizing leukoencephalopathy which was most severe in the occipital lobes. The medullary pyramids and posterior columns were also severely affected. This sporadic fatal neurotoxicity was observed only at doses greater than 40 mg/m2/day. The maximum tolerated dose for a 5-day infusion of fludarabine phosphate is thus 40 mg/m2/day.

Acidosis↗
PubMed1986

The treatment of myelodysplastic syndromes.

The available data fail to support a standard therapy for MDS. Any therapy should therefore, include participation in a well designed clinical trial. The MDS include patients with a variety of prognoses. Since most studies show that death from infection and bleeding are more likely than progression to frank leukaemia, attention to supportive care is crucial for all patients with MDS. Some patients with MDS may be successfully supported with transfusions and observation for prolonged periods. Patients with significant comorbid disease or patients without increased marrow myeloblasts are good candidates for this conservative approach. Conversely, young patients have a better likelihood of benefit from aggressive therapy, and intensive chemotherapy or allogenic bone marrow transplantation should be considered. Patients with preleukaemia related to prior cytotoxic therapy are another poor prognosis group for whom aggressive therapy may be the best alternative. Therapy with low-dose ara-C or other differentiating agents should be considered investigational and unproven until comparative trials can demonstrate a definitive survival advantage. In addition to comparative trials, innovative clinical studies are needed to address differentiation as an in vivo mechanism of action and its importance in MDS therapy.

Adult↗