PubMed Health⌕ Search

Biomedical subjects

G Morstyn

Publications and source records attributed to G Morstyn.

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

Effect of recombinant human granulocyte-macrophage colony stimulating factor on progenitor cells in patients with advanced malignancies.

Haemopoietic progenitor cell levels were determined in the blood and marrow of 37 patients with advanced malignancies undergoing a phase I/II clinical trial of 0.3-30 micrograms/kg/d recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF). After injection of rGM-CSF, the absolute number of circulating progenitor cells fell initially but after 4 d of infusion a dose-dependent increase was observed in progenitor cells of all lineages with a slight bias favouring granulocyte-macrophage progenitors. A mean 8.4-fold increase in GM-CFC and a 3.3-fold increase in BFU-E were observed at a dose level of 20 micrograms/kg/d of rGM-CSF. Patients with malignant lymphoma showed a greater response than other patients at the same dose level and the CFU-E rise correlated with the haematocrit. This study suggests that GM-CSF may be of value in elevating circulating progenitor cells for subsequent autografting.

Adult↗
PubMed1990

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF): identification of a binding site for a neutralizing antibody.

One approach to the localization of functionally active regions of human granulocyte-macrophage colony-stimulating factor (hGM-CSF) is to map the epitopes recognized by neutralizing anti-hGM-CSF monoclonal antibodies. We have defined the epitope recognized by one neutralizing antibody (LMM102) using proteolytic fragments obtained by enzymic digestion of bacterially synthesized hGM-CSF. RP-HPLC fractionation of a tryptic digest resulted in the identification of an immunoreactive "tryptic core" peptide containing 66 amino acids (52% of the protein). Further digestion of this "tryptic core" with S. aureus V8 protease produced a unique immunoreactive hGM-CSF product comprising two peptides, residues 86-93 and 112-127, linked by a disulfide bond between residues 88 and 121. The individual peptides, generated by reduction with dithiothreitol, were not recognized by the antibody. An analog of this peptide has been synthesized chemically and shown to have similar immunoreactivity to the epitope obtained by enzymic digestion. A series of modified peptides has also been synthesized to identify further the region required for antibody recognition.

Amino Acid Sequence↗
PubMed1990

The potential role of granulocyte-macrophage colony stimulating factor (GM-CSF) in cancer chemotherapy.

GM-CSF has been used in clinical trials to assess its role in promoting the proliferation and differentiation of marrow cells and enhancing the functional activities of granulocytes and monocytes. These studies have indicated that GM-CSF may prove useful in the management of cancer patients by preventing or treating myelosuppression following cancer chemotherapy and in patients with myelodysplasia or aplastic anaemia. As well as determining the efficacy of GM-CSF as a therapeutic agent, these studies are also providing insights into the possible roles of GM-CSF in vivo. Pharmacokinetic studies of GM-CSF in patients with advanced cancer and myelodysplasia suggest that the ratio of efficacy to toxicity of GM-CSF can be modified by changing either the dose or the method of administration.

Bone Marrow Transplantation↗
PubMed1989

Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation.

Granulocyte colony-stimulating factor (G-CSF) was administered by continuous subcutaneous infusion to 15 patients with non-myeloid malignancies treated by high-dose chemotherapy and autologous bone marrow infusion. G-CSF was given at variable dosage based on neutrophil count. Sustained serum levels of G-CSF were achieved. Neutrophil recovery was accelerated in G-CSF treated patients compared with 18 historical controls and exceeded 0.5 x 10(9)/l at a mean of 11 days after marrow infusion compared with 20 days for controls, a significant difference. This reduction led to significantly fewer days of parenteral antibiotic therapy, 11 versus 18 days in controls, and less isolation in reverse-barrier nursing, 10 versus 18 days.

Agranulocytosis↗
PubMed1989

Pharmacology of the colony-stimulating factors.

Leukocyte production is influenced by a family of glycoproteins called colony-stimulating factors. Two of these have been purified, cloned and produced in quantities sufficient for clinical use. Granulocyte colony-stimulating factor (G-CSF) preferentially stimulates neutrophil production and has been shown to reduce the duration of neutropenia following chemotherapy. G-CSF therapy also has beneficial effects in a variety of other neutropenic states. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates neutrophil, monocyte and eosinophil production and function. GM-CSF is associated with more diverse haematological and clinical effects. George Morstyn and colleagues summarize the promising results from the early clinical trials with these new therapeutic agents.

Animals↗
PubMed1989

Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy.

In patients who have not received extensive prior chemotherapy or radiotherapy, it has been previously demonstrated that granulocyte colony-stimulating factor (G-CSF) abrogated the leukopenia following administration of melphalan (25 mg/m2). This study examined the necessity of a prechemotherapy period of G-CSF administration and the effect of varying the timing and duration of postchemotherapy G-CSF. Initially, patients received 0.3, 1.0, 3.0, and 10 micrograms/kg/d subcutaneously on days 1 to 5 and days 10 to 18. Melphalan was given on day 9. In the next portion of the study melphalan was administered on day 1 and G-CSF, 10 micrograms/kg/d, was administered by subcutaneous infusion on five schedules: (1) days 2 to 13; (2) days 8 to 13; (3) days 2 to 18; (4) days 8 to 18; (5) days -9 to -2 and 2 to 13. G-CSF produced a rapid and sustained elevation in neutrophil levels within 24 hours even when started 8 days after melphalan. This treatment was sufficient to abrogate the neutropenia in patients who had received no prior chemotherapy. It was not necessary to continue G-CSF for more than 7 days. G-CSF did not consistently alter the course of the thrombocytopenia that followed this dose of melphalan. G-CSF was well tolerated, although mild bone pain occurred and was reduced with acetaminophen. One of 22 patients developed cellulitis at an infusion site. We conclude that after melphalan chemotherapy, G-CSF may need to be given for only a short period to prevent chemotherapy-induced neutropenia, and that G-CSF induces a rapid rise in neutrophil levels even when started 8 days after melphalan administration.

Adult↗
PubMed1989

Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor.

Bacterially synthesized human granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) have been studied to determine if they could prevent or reduce the neutropenia caused by chemotherapy. Our studies suggest that 10 micrograms/kg/day of G-CSF administered as a continuous subcutaneous infusion abrogates the neutropenia associated with a standard dose of melphalan. G-CSF produced a rapid increase of neutrophil levels, was well-tolerated, and was associated with only one frequent adverse effect: bone pain. GM-CSF, administered in doses ranging from 3 to 15 micrograms/kg/day subcutaneously, appeared to be useful in abrogating the neutropenia associated with chemotherapy, producing elevations in neutrophils, eosinophils, and monocytes. Although GM-CSF was relatively well-tolerated, several adverse effects, including bone pain, rashes, and fluid retention, were observed. The initial dose of GM-CSF in some patients produced a reaction that was characterized by hypoxia.

Clinical Trials as Topic↗
PubMed1989

Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor.

As part of phase I/II clinical trials of granulocyte colony-stimulating factor (G-CSF), the pharmacokinetics was studied. To determine the optimal way of abrogating the neutropenia caused by melphalan, patients received G-CSF and melphalan on several schedules. The half-life (t 1/2) of elimination of G-CSF was in the range 1.3 to 4.2 hours and was prolonged at higher doses, suggesting that one clearance mechanism becomes saturated at doses greater than 10 micrograms/kg, When a continuous subcutaneous (SC) infusion was administered for five days, a rapid reduction in serum G-CSF levels occurred during the last two days of the infusion, indicating that an additional clearance mechanism was induced. When a continuous infusion of G-CSF was administered after melphalan, serum G-CSF levels remained constant for a longer period of time but did decrease during the second phase of a biphasic neutrophil response. In another clinical trial, G-CSF was administered after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). In these patients, the G-CSF levels did not decrease while the patients were neutropenic. These results show that increased neutrophil levels are associated with increased clearance of G-CSF. This may be one of the negative feedback mechanisms involved in maintaining neutrophil homeostasis in normal and disease states.

Cell Differentiation↗
PubMed1989

Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor.

Bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is an agent with therapeutic potential for neutropenic states, but even at doses below the maximal tolerated dose adverse effects occur during short courses of administration. We have recognized a syndrome of hypoxia and hypotension that follows the first but not subsequent doses of rhGM-CSF. Thirteen of 42 patients receiving rhGM-CSF in phase I studies and 4 of 6 patients in a phase II study developed a reaction that occurred after the first dose of 24 of 78 cycles of rhGM-CSF therapy. The reaction was characterized by flushing (16 of 24), tachycardia (16 of 24), hypotension (14 of 24), musculoskeletal pain (13 of 24), dyspnea (12 of 24), nausea and vomiting (11 of 24), rigors (5 of 24), involuntary leg spasms (3 of 24), and syncope (3 of 24). The reaction did not occur after any of more than 600 second and subsequent consecutive rhGM-CSF doses. Oxygen saturation decreased during first-dose reactions by 8% +/- 4% as compared with 3% +/- 1% on first days without reactions (P less than .001) and 2% +/- 1% on subsequent days (P less than .001). Pulmonary dysfunction was characterized by hypoxemia (59 +/- 9 mm Hg, mean +/- SD) that was fully correctable with supplementary oxygen, decreased single-breath carbon monoxide diffusion capacity, and increased alveolar-arterial oxygen gradients (25 +/- 6 to 60 +/- 4 mm Hg, mean +/- SD), but no significant abnormalities on chest roentgenogram or lung perfusion scan. Factors predisposing to reactions were rhGM-CSF dose greater than or equal to 3 micrograms/kg (P less than .01), intravenous (IV) rather than subcutaneous (SC) administration (P less than .05), occurrence of a reaction after the first dose of a previous cycle of rhGM-CSF therapy (P less than .01), and for patients receiving 15 micrograms/kg/d by SC bolus, the presence of lung cancer (P less than .05). Administration of 15 micrograms/kg/d rhGM-CSF by 24-hour SC infusion rather than SC bolus resulted in a delayed onset of reaction from 30 +/- 8 minutes to 240 +/- 190 minutes (mean +/- SD, P less than .001), and a slower rate of initial transient decrease in neutrophil levels and a more prolonged duration of transient leukopenia. The time of onset of reactions correlated with the rate of rise of rhGM-CSF levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Colony-Stimulating Factors↗
PubMed1989

Empiric single agent or combination antibiotic therapy for febrile episodes in neutropenic patients: an overview.

Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granulocytopenia leaves leukaemic patients at greatest risk of breakthrough or second infections. These patients therefore appear to be the most likely to benefit from the clinical use of haemopoietic growth factors such as granulocyte and granulocyte-macrophage colony-stimulating factor.

Agranulocytosis↗
PubMed1988

Hemopoietic growth factors: a review.

Several hemopoietic growth factors have now been purified, cloned, and produced in bacteria. Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor are already being used in clinical trials. Within 12 months two more hemopoietic growth factors, macrophage colony stimulating factor (also called colony stimulating factor 1) and interleukin 3 (also called multi-colony stimulating factor) will be used for patient treatment. This review discusses the recent advances in our knowledge of the molecular properties and biological specificities of these factors. It is now clear that these molecules are able to modulate selectively the activity of mature blood cells as well as stimulating the production of specific lineages of blood cells. The availability of recombinant hemopoietic growth factors purified from animal or yeast cell conditioned medium or bacteria has facilitated in vivo experiments, as well as the clinical trials. Each of the growth factors has a unique spectrum of biological activities and it appears that the growth factors will enhance the recovery and function of circulating white blood cells after cancer therapy or bone marrow transplantation.

Animals↗
PubMed1988

Effects of bombesin antagonists on the growth of small cell lung cancer cells in vitro.

Small cell lung cancer (SCLC) produces several neuroendocrine peptides, including gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin. There is some evidence to support the suggestion that GRP is an autocrine regulator of SCLC growth. Therefore, we have tested the effect of bombesin and two antagonists of bombesin on SCLC cell growth in a serum-free liquid tissue culture system. The antagonists used were analogues of substance P: spantide and (D-Arg1, D-Pro2, D-Trp7,9, Leu11) substance P. The cell lines used in this study all produced GRP-related peptides and one line had demonstrable GRP receptors. Exogenous bombesin did not cause any stimulation of growth in the liquid culture assay. The bombesin antagonists inhibited SCLC cell growth, but apparently not via the bombesin receptor. The bombesin used was biologically active because it stimulated the proliferation of Swiss 3T3 fibroblasts. The antagonists caused inhibition of this bombesin-induced proliferation, which was reversed by addition of excess bombesin. In addition, the antagonists and substance P alone stimulated proliferation of 3T3 cells, indicating that they may interact with another growth factor receptor on 3T3 cells. We conclude that growth of SCLC cells is not dependent on bombesin under all in vitro culture conditions because bombesin failed to stimulate growth in liquid cultures and the growth inhibition caused by bombesin antagonists was probably not mediated by the bombesin receptor.

Animals↗
PubMed1988

Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy.

A phase I/II study of granulocyte colony stimulating factor (G-CSF) was undertaken in patients with advanced malignancy receiving melphalan to determine the granulocyte response, side-effects, and pharmacokinetics. Patients received doses of 1-60 micrograms/kg intravenously. There were 3 patients at each dose level. Before chemotherapy the immediate effect of G-CSF was a transient depression in circulating neutrophils followed by a dose-dependent rise. Neutrophil counts up to 80 X 10(9)/l were achieved. G-CSF administration following melphalan reduced the period of neutropenia caused by melphalan. G-CSF was well tolerated and the only clinical observation that appeared related to G-CSF administration was slight bone pain during some infusions. G-CSF was rapidly cleared from the blood with a mean half-life of 110 min for the second phase. Reductions in the number of days of neutropenia following cytotoxic chemotherapy may reduce the morbidity and mortality of chemotherapy.

Aged↗