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M A Moore

Publications and source records attributed to M A Moore.

At least 235 records · Page 13Linked to original sources
PubMed1990

Tumor-necrosis factor induces cell cycle arrest in multipotential hematopoietic stem cells: a possible radioprotective mechanism.

Tumor-necrosis factor (TNF) and interleukin-1 (IL-1) have been shown to confer protection of hematopoiesis in mice challenged with radiation. Herein, a series of experiments designed to elucidate the underlying mechanism is presented. After TNF administration, colony-stimulating activity, but no IL-1 activity, was detectable in mouse plasma. In endogenous CFU-S assays, TNF enhanced the survival of multipotential progenitors when administered before, but not after, irradiation. In experiments with fractionated irradiation, the radioprotective effect of TNF was distinctly different from that of IL-1. In vivo and in vitro thymidine suicide assays demonstrated that TNF wholly or partially abolished cell cycling of the CFU-S hematopoietic compartment. These data imply that TNF may inhibit the cell cycle in hematopoietic progenitor cell populations.

Animals↗
PubMed1990

Haemopoietic growth factor interactions: in vitro and in vivo preclinical evaluation.

Proliferation and differentiation within the haemopoietic system is closely regulated by a family of haemopoietic growth factors. To date, nine interleukins (IL), three colony stimulating factors (CSF) and erythropoietin (Epo) have been implicated in control of haemopoiesis and lymphopoiesis. These cytokines form a family of glycoproteins with pleiotropic effects at different levels. Certain factors (IL-1, IL-6, IL-3) are active at the level of the pluripotential stem cell, whereas others (eg macrophage-CSF, granulocyte-CSF, Epo) facilitate differentiation of lineage restricted cell populations. The cytokines are inducible products of a variety of cell types of which T lymphocytes, macrophages, endothelial cells and fibroblasts are of particular importance. High affinity receptors for all of these factors have been identified, characterized and, in a number of cases, the genes for the receptors have been cloned. Regulation of haemopoiesis involves (a) transcriptional and translational control of cytokine gene expression; (b) post-translational modification of cytokines; (3) receptor downregulation, upregulation, and trans-down modulation; and (d) redistribution of stem cells and progenitor cells to different microenvironments. In vivo administration of these factors in normal animals and in situations of myelosuppression following chemotherapy or irradiation has revealed their efficacy in stimulating various pathways of haemopoiesis. An understanding of the mechanism of action of these factors is providing a rationale for future clinical applications in appropriate combinations.

Animals↗
PubMed1989

Modulation of colony-stimulating factor-1 receptors on macrophages by tumor necrosis factor.

The effect of murine rTNF-alpha on the binding of human 125I-rCSF-1 to murine thioglycolate-elicited peritoneal exudate macrophages (PEM) was investigated. At 4 degrees C, 125I-CSF-1 binding to PEM was inhibited by preincubation with human rCSF-1, but not by other cytokines. When PEM were incubated with various cytokines at 37 degrees C, murine rTNF-alpha caused greater than 90% decrease in 125I-CSF-1 binding. This decrease was time, temperature and TNF dose dependent, and was not affected by preincubation with cycloheximide. The reduction in CSF-1-binding activity was reversed by prolonged incubation at 37 degrees C even in the presence of TNF. However, PEM preincubated with TNF subsequently washing free of residual TNF resulted in a rapid recovery of CSF-1 binding. This recovery of CSF-1-binding activity required protein synthesis. Binding studies suggested that the decrease in 125I-CSF-1 binding was most likely caused by a reduction in the number of CSF-1 receptors. In addition, preincubation with TNF at 37 degrees C inhibited 125I-CSF-1 binding on mononuclear phagocytes, including the macrophage cell line J774, bone marrow-derived macrophages, and nonelicited macrophages from three different strains of mice. In contrast, 125I-murine rTNF-alpha binding to PEM was not inhibited by preincubation with CSF-1 at 4 degrees C or 37 degrees C. These data suggest that TNF may play a role in the modulation of receptor expression on blood cells, and may point to a role for this pleiotropic cytokine in the regulation of hemopoiesis.

Animals↗
PubMed1989

Clinical use of recombinant human hematopoietic growth factors.

Hematopoietic growth factors comprise a family of hematopoietic regulators with biologic specificities defined by their ability to support proliferation and differentiation of blood cells of different lineages. The biologic specificities of these factors are highly complex, dose dependent, and frequently overlapping. Recent advances in the cloning of hematopoietic growth factor genes and the availability of recombinant material have led investigators to conduct clinical trials with these agents. Some of these factors have been studied and used in chemotherapy-induced neutropenia, myelodysplastic syndromes, and bone marrow failure syndromes. In this paper, we review the experience with growth factors that have been tested and that currently are being introduced in clinical trials. In addition, we report some factors with possible future interest for clinicians and researchers.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Effects of interleukin-1 on hematopoietic progenitors: evidence of stimulatory and inhibitory activities in a primate model.

The effects of recombinant human interleukin-1 rhIL-1 beta (rhIL-1b) on hematopoietic recovery following chemotherapy in a primate model were investigated. Cynomolgus monkeys received 1 microgram/kg/day rhIL-1b intravenously for 2, 7, and 14 days following 5-Fluorouracil (5-FU) treatment (75 mg/kg x 2 days). Compared with controls, a significantly shortened time to achieve an absolute neutrophil (ANC) count over 500/microL was observed in animals receiving 2- and 7-day courses of rhIL-1b (17 v 30 days), while animals receiving a 14-day course of rhIL-1b achieved an ANC over 500/microL by 23 days. Concomitantly, a marked increase in granulocyte-macrophage colonies (CFU-GM) was observed at 14 days following 5-FU in animals receiving 2- and 7-day rhIL-1b courses. In animals receiving a 14-day rhIL-1b course, a significant increase in CFU-GM relative to control was not seen until 21 days post 5-FU. Utilizing a serum-free colony assay system, a 50% inhibition of normal marrow CFU-GM growth was observed with the addition of sera obtained on day 9 post 5-FU from animals receiving rhIL-1b for 14 days. Sera obtained at any time from animals receiving 2- and 7-day rhIL-1b treatment did not show any growth inhibition. Addition of antibodies to TNFa to the coculture assay abrogated the CFU-GM growth inhibition. TNFa levels in sera with the inhibitory activity was relatively high (918 pg/mL). Our data indicate that rhIL-1b enhances hematopoietic recovery following 5-FU if administered for short periods of time (less than 7 days), whereas prolonged administration has a counterproductive effect that is due in part to the induction of TNFa production.

Animals↗
PubMed1989

Effect of recombinant murine tumor necrosis factor on hemopoietic reconstitution in sublethally irradiated mice.

Intravenous bolus administration of a single 2-micrograms dose of murine rTNF-alpha to BALB/c mice 20 h before sublethal total-body irradiation (7.5 Gy) conferred significant protection against radiation-induced leukopenia. Murine rTNF-alpha administration not only reduced the decline of neutrophil and total blood cell counts after radiation, but also accelerated the subsequent normalization of peripheral blood cell counts. This was accompanied by accelerated regeneration of primitive hematopoietic progenitors, as determined by the in vivo spleen CFU assay, and the in vitro assay of the more mature hematopoietic cell compartment. This demonstrates that pretreatment with murine rTNF-alpha enhances hematopoietic reconstitution after sublethal irradiation, and indicates a possible therapeutic potential for this agent in the treatment of radiation-induced myelo-suppression.

Animals↗
PubMed1989

Colony-stimulating factors. A panel discussion.

One of the most exciting recent developments in cancer-related research has been the discovery and understanding of colony-stimulating factors. There is now a general optimism that these factors will be used in the treatment of a variety of solid tumors, lymphomas, and leukemias, as well as in the treatment of patients who are immunocompromised or undergoing bone marrow transplantation. We have gathered a distinguished panel of experts to discuss the current status of this rapidly moving field.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Effects of IL-1 on hematopoietic progenitors after myelosuppressive chemoradiotherapy.

Recently it has been recognized that IL-1 plays an important role in hematopoietic regulation. Administration of 5-fluorouracil (5-FU) to mice causes prolonged neutropenia. rHIL-1 injected to mice after 5-FU, accelerated the recovery of hematopoietic progenitors and blood neutrophils. The combination of rhIL-1 and rhG-CSF reduced the neutropenic period significantly. Sublethal irradiation of mice induced profound neutropenia for 3 weeks which was associated with 80% mortality. Administration of rhIL-1 20 hours prior to or 2 hours post irradiation resulted in a significantly improved survival and rapid recovery of the neutrophil count. IL-1 administered alone or in combination with other colony stimulating factors to spontaneous breast tumor bearing mice following 5-FU therapy resulted in a rapid recovery of neutrophils, improved survival, and markedly reduced the tumor mass. Experiments in primates demonstrated that rhIL-1 administered to 5-FU treated animals shortened the neutropenic period from 30 to 17 days and increased the number of marrow progenitors responsive to other CSFs. Prolonged administration of IL-1 (14 days) to these animals resulted in a delayed neutrophil recovery as compared to animals receiving short courses of IL-1. rhIL-1 administered to primates receiving marrow grafts after lethal irradiation, did not result in rapid hematopoietic recovery. In humans, studies with CD-34 positive marrow cells showed that IL-1 had a radioprotective effect on a committed and early marrow progenitors. These data show the therapeutic potential of IL-1 in the treatment of chemoradiotherapy induced myelosuppression.

Animals↗
PubMed1989

Adrenal cortical foci and nodules in Sprague-Dawley rats treated with N-nitrosomorpholine. Light and electron microscopic findings.

Treatment of male Sprague-Dawley rats with N-nitrosomorpholine (NNM) in the drinking water at a dose of 120 mg/l for 7 weeks resulted in a subsequent enhanced development of focal and nodular lesions in the adrenal cortex. Sequential observation revealed that focal lesions in the zona reticularis/fasciculata or the zona glomerulosa developed both earlier and at a significantly higher incidence in animals treated with carcinogen than in untreated controls. Foci observed within or adjacent to the zona glomerulosa were all of pale cell appearance and contained large numbers of electron-dense cytoplasmic granules similar to those observed in normal granulosa cells. The foci and nodules which arose in the zona reticularis/fasciculata were, in contrast, characterized by a reduction or loss of the dense osmiophilic droplets normally seen in the cells of this region of the adrenal cortex, a pronounced increase in pleomorphic mitochondria of atypical appearance and the development of vacuoles.

Adrenal Cortex Neoplasms↗
PubMed1989

Modifying influence of dehydroepiandrosterone or butylated hydroxytoluene treatment on initiation and development stages of azaserine-induced acinar pancreatic preneoplastic lesions in the rat.

Dietary administration of dehydroepiandrosterone (DHEA) (0.6%) or butylated hydroxytoluene (BHT) (1%) during or subsequent to two i.p. injections of azaserine (30 mg/kg body wt) resulted in significant alteration of yield of preneoplastic lesions in both pancreas and liver. While concomitant application appeared not to have any effect on subsequent development of glutathione S-transferase P form (GST-P) positive hepatocellular lesions in either case, BHT and to a lesser extent also DHEA reduced initiation of pancreatic acinar carcinogenesis. Both BHT and DHEA were associated with significant increase in GST-A form positive pancreatic foci when administered after cessation of carcinogen treatment while clearly inhibiting liver lesion development. The results point to a marked differential in the response of the liver and pancreas to external stimulus with regard to preneoplastic focal lesions while demonstrating significant second stage promotion of pancreatic acinar carcinogenesis by BHT and DHEA.

Animals↗
PubMed1989

Radioprotection by murine and human tumor-necrosis factor: dose-dependent effects on hematopoiesis in the mouse.

Tumor-necrosis factor (TNF) has been shown to confer significant radioprotection in murine models. Herein, we demonstrate a dose-dependent enhancement of hematological recovery when single doses of either murine or human recombinant TNF are administered prior to irradiation. In addition to its action upon leukocytes and erythrocytes, TNF also alleviates radiation-induced thrombocytopenia in the mouse. These effects on circulating blood constituents are further reflected in increased numbers of both primitive (CFU-S) and more differentiated (CFU-GM, CFU-Mega) hematopoietic progenitors in TNF-treated animals. This suggests that TNF exerts it radioprotective effects on a pool of primitive multi-potential hematopoietic cells.

Animals↗
PubMed1989

Presence of tumour necrosis factor or a related factor in human basophil/mast cells.

The observation that mast cell products and cachectin/tumour necrosis factor (TNF) mediate similar responses suggested an investigation of cultured human basophil/mast cells for production of TNF. Using in situ hybridization and the avidin biotin-complex (ABC) immunoperoxidase method, we have demonstrated the presence of TNF mRNA in the cytoplasm and TNF protein in the granules of individual human basophil/mast cells. The production of TNF by these cells could explain many of their reported functions.

Basophils↗
PubMed1988

Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium.

We evaluated the ability of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to prevent chemotherapy-induced neutropenia or to accelerate recovery from this complication and thus allow patients to receive full doses of antineoplastic agents on time, according to protocol design. Twenty-seven patients with transitional-cell carcinoma of the urothelium who were undergoing treatment with methotrexate, doxorubicin, vinblastine, and cisplatin were given rhG-CSF (up to 60 micrograms per kilogram of body weight per day) before their first cycle of combination chemotherapy, during the first cycle, or at both points. Treatment with rhG-CSF before chemotherapy resulted in a dose-dependent increase in the absolute neutrophil count. Treatment with rhG-CSF after chemotherapy significantly reduced the number of days (91 percent) per patient on which the absolute neutrophil count was 1000 per microliter or less (P = 0.0039), reduced the number of days (1 vs. 35) on which antibiotics were used to treat fever and neutropenia, and significantly increased the percentage (100 vs. 29 percent) of patients qualified to receive planned chemotherapy on day 14 of the treatment cycle (P = 0.0015). In addition, the incidence of mucositis was significantly decreased (11 vs. 44 percent, P = 0.041), as was its severity. These findings demonstrate that rhG-CSF is a potent stimulus of normal neutrophil proliferation and maturation. In addition, its administration can reduce both the hematopoietic and oral toxicity of chemotherapy.

Adult↗
PubMed1988

Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3.

Normal human T cells purified from the peripheral blood and cultured for 6 days in the presence of OKT3 and IL-2 were shown to produce simultaneously TNF and lymphotoxin (LT) mRNA. Both biologically active TNF and LT were detected in supernatants of the cultured T cells using WEHI 164 as target cells. The cytotoxic activities of both cytokines could be inhibited with specific antibodies against TNF or LT. The T cell cultures were free of macrophages, NK cells, or B lymphocytes as assessed by flow cytometric analysis.

Antibodies, Monoclonal↗