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Biomedical subjects

G Morstyn

Publications and source records attributed to G Morstyn.

At least 37 records · Page 2Linked to original sources
PubMed1992

Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation.

Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.

Adolescent↗
PubMed1992

Marrow proliferation and the appearance of giant neutrophils in response to recombinant human granulocyte colony stimulating factor (rhG-CSF).

During a study of recombinant human granulocyte colony stimulating factor (rhG-CSF) administration, 15 patients received twice daily i.v. infusions and nine patients received daily s.c. infusions of rhG-CSF for 5 d prior to cytotoxic therapy, and then a second course subsequent to melphalan administration. There was a striking dose-related neutrophilia and the appearance in the blood of early myeloid cells that express the intercellular adhesion molecule CD54. In addition, giant neutrophils or macropolycytes were observed in the peripheral blood of all patients. These cells were evident on the display of the Technicon H*1 as a population of large peroxidase positive cells, and using Feulgen staining these cells were shown to be tetraploid. Bone marrow kinetics studies performed on Day 4 or 5 indicated an increase in the proportion of bone marrow cells in S phase, G2 and mitosis, reflecting a proliferative response of the marrow. Large myeloid precursors and occasional binucleate promyelocytes were seen in the bone marrows done on Days 14 and 18 but not on Day 5. These findings indicate that administered G-CSF has both quantitative and qualitative effects on myeloid cells in vivo.

Bone Marrow↗
PubMed1992

The dissociation of GM-CSF efficacy from toxicity according to route of administration: a pharmacodynamic study.

The pharmacokinetics and pharmacodynamics of bacterially synthesized granulocyte-macrophage colony stimulating factor (GM-CSF) were studied in 33 patients. GM-CSF (0.3-30 micrograms/kg/d) was administered subcutaneously (s.c.) or intravenously (i.v.) by bolus or 2 h infusion for 10 d to three patients at each dose level, and serum levels measured by enzyme-linked immunosorbent assay (ELISA). Relationships between pharmacokinetic variables and GM-CSF efficacy and toxicity were investigated. GM-CSF appeared more effective s.c. than i.v. Correlations with response improved when patients with neutropenia or marrow infiltration by tumour were excluded. For the remaining patients, the correlation coefficients between the day 10 leucocyte count was highest with dose (R = 0.629, P less than 0.01), the duration GM-CSF concentrations exceeded 1 ng/ml (r = 0.524, P less than 0.05) and area under the concentration-time curve (R = 0.508, P less than 0.05). There was no correlation with peak serum GM-CSF (Cmax) (R = 0.188, P = NS). In contrast, the first dose reaction (characterized by hypoxaemia and hypotension) was associated with high Cmax (P less than 0.01) and i.v. administration. Fever, liver enzyme elevation and pericarditis occurred at 10-30 micrograms/kg and were not influenced by route. Since the variables correlating with response differed from those correlating with these toxicities, it appears that the therapeutic index for GM-CSF can be increased by modifying the method of administration.

Dose-Response Relationship, Drug↗
PubMed1992

Carboplatin-containing regimens for small cell lung cancer: implications for management in the elderly.

The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response rates of 77% and 85% were noted for the two- and four-drug regimens, respectively, among patients with limited disease (LD). Response rates among patients with extensive disease (ED) were 58% and 79%, respectively. The profiles of nonhematologic toxicity were modest; myelosuppression was dose-limiting when colony-stimulating factors were not used. Twenty-six patients (14%) were older than 70 years of age. Although hematologic toxicity was more severe in the elderly group, there was no significant difference in nonhematologic toxicity, response rate, or overall survival between the geriatric and younger groups. When LD only was considered, 33% of those younger than 70 were alive at 2 years; no patients aged 70 years or older with LD were alive beyond 2 years. In patients with ED, there was no age-related difference in survival. Cytotoxic regimens based on etoposide/carboplatin constitute useful treatment for SCLC, with high response rates and manageable toxicity, irrespective of patient age.

Adult↗
PubMed1991

Identification of a functional domain of human granulocyte colony-stimulating factor using neutralizing monoclonal antibodies.

Human granulocyte colony-stimulating factor (G-CSF) is a hemopoietic growth factor that is being used successfully to treat various forms of neutropenia. To define functionally important regions of G-CSF, we have prepared 37 monoclonal anti-G-CSF antibodies and mapped the regions of G-CSF recognized by different antibody groups. Antibodies recognizing similar epitopes were identified by competition assays, neutralization assays, conformation dependence and cross-reactivity with canine G-CSF. Seven of eight neutralizing antibodies fell into two related epitope groups and were conformation-dependent. The eighth was unrelated and conformation-independent. Peptides of G-CSF were generated by chemical or enzymatic digestion and tested for antibody reactivity. One of the neutralizing antibodies (LMM351) recognized a small, disulfide-bonded peptide from the V8 protease digest (residues 34-46). A synthetic peptide (residues 20-58) was recognized by all the neutralizing antibodies, implicating this disulfide-bonded loop in receptor binding. The epitopes recognized by nonneutralizing antibodies were found throughout G-CSF. Thus, regions of G-CSF that are not involved in receptor binding have also been defined. A CNBr peptide (residues 1-121) had greatly reduced biological activity, indicating that the COOH terminus is required for receptor binding. We predict that residues 20-46 and the COOH terminus bind to the G-CSF receptor.

Amino Acid Sequence↗
PubMed1991

Characterisation of a cell line (LCC-18) from a cultured human neuroendocrine-differentiated colonic carcinoma.

A cell line (LCC-18) from a neuroendocrine colonic tumour was established. The tumour cells retained their endocrine characteristics through more than 100 passages and showed positive immunocytochemistry for synaptophysin, vasoactive intestinal polypeptide (VIP) and glucagon. The culture medium also contained VIP and glucagon, which indicates that mechanisms for release of some of the active peptides were preserved. Transplantation of LCC-18 tumour cells into nude rats resulted in tumour formation with similar endocrine characteristics. The c-myc gene was amplified which might have been a prerequisite for establishment of the cell line. The chromosomes in LCC-18 were studied by G-banding and C-banding. The cell line had a distinctive mode in the hypotriploid region, at S = 61. The double minute (Dms) positive stemline karyotype showed numerical and structural aberrations more similar to findings in ordinary colonic adenocarcinomas than to observations in previously studied, pure intestinal neuroendocrine tumours. The Dms may be correlated with amplification of c-myc. LCC-18 may become valuable for studies of neuroendocrine differentiation, regulation of growth and production and release of hormones and for studies of drug effect.

Adult↗
PubMed1991

Human interleukin-4: an immunomodulator with potential therapeutic applications.

Human interleukin-4 (IL-4) is a 20kDa cytokine produced by activated T cells and has an extensive range of stimulatory and inhibitory effects on the wide range of cells which express its receptor. It specifically promotes the immunoglobulin class switch to IgE and IgG4 and potently co-stimulates with CD40 monoclonal antibodies the long term proliferation of human B cells. It has variable effects on T cells, but predominantly has inhibitory actions on monocytes suggesting a potential therapeutic role as an anti-inflammatory agent. There is evidence for indirect anti-cancer activity of IL-4 both in animal models and in in vitro studies on human tumour infiltrating lymphocytes. In addition, IL-4 directly inhibits the in vitro proliferation of the majority of B cell neoplasms. Phase I studies of IL-4 in patients with cancer have commenced and promising observations have been made in patients with haematological malignancies receiving low, well-tolerated doses.

Adjuvants, Immunologic↗
PubMed1991

Clinical profile in Barrett's esophagus: who should be screened for cancer?

A retrospective survey identified 96 patients (58 males) with Barrett's esophagus, diagnosed at the Royal Melbourne Hospital between 1978 and 1986. The age at presentation varied from 20 to 93 years, and 43% were greater than 70 years. Heartburn was a presenting symptom in 71%, regurgitation into the pharynx in 54%, dysphagia in 31% and hematemesis or melena in 29%. At endoscopy, the length of Barrett's epithelium ranged from 3 cm to 15 cm. Macroscopic esophagitis was observed in 69%, benign esophageal strictures in 14% and a co-existent adenocarcinoma of the lower esophagus in 10% of patients. Only 30% of the patients were cigarette smokers at the time of diagnosis, but 64% drank alcohol (9% greater than 80 g alcohol daily). Patients with esophageal cancer at presentation were more likely to be male and cigarette smokers (Fisher's exact probability test). It has been suggested that patients with Barrett's esophagus should be screened to detect the early development of esophageal cancer. If patients who already have cancer, the elderly (age greater than 70 years) and those with a chronic alcohol problem (greater than 80 g intake daily) are excluded from endoscopic cancer surveillance, only 42% of the patients described in this survey would be eligible for enrollment in such a program. This represents a recruitment of only 5 new patients yearly in a large teaching hospital endoscopy unit.

Adenocarcinoma↗
PubMed1990

Pharmacokinetics and toxicity of two schedules of high dose epirubicin.

Epirubicin, a stereoisomer of doxorubicin, is reported to have equal antitumor activity with lower cardiac and systemic toxicity. Recently the maximum tolerated dose of this drug has been revised upwards with reported increased response rates. However, the pharmacokinetics of epirubicin at high doses have never been reported. Accordingly, this study was designed to evaluate the pharmacokinetics of epirubicin when administered as either a 15-min i.v. bolus or a 6-h i.v. infusion in a phase I study at high doses. Nineteen patients with a variety of malignancies were given a total of 52 cycles of epirubicin at doses of 90 to 150 mg/m2 given once every 3 weeks. The maximum tolerated dose was 150 mg/m2 epirubicin given either as a bolus or as an infusion. The major dose-limiting toxicity was neutropenia. Interpatient variation occurred in the pharmacokinetics at each dose level but overall there were dose-dependent pharmacokinetics. This was manifested as a disproportionate increase in plasma levels and areas under the curve as the epirubicin dose was increased from 90 to 150 mg/m2. The pharmacokinetics of epirubicin could best be described by an open two-compartment model. Peak plasma concentrations were attained at a median of 12 min following the bolus injection and concentrations approached the steady state within a median of 55 min following the start of the 6-h infusion. Administration of the 150 mg/m2 dose over the 6 h compared to the bolus administration was associated with a 92% decrease in peak concentration from 3088 +/- 1503 to 234 +/- 126 ng/ml. This was not associated with an appreciable change in hematological or nonhematological toxicities. The median distribution half-life was 10 min and the median elimination half-life was 42.0 h. The cumulative renal excretion of the parent compound accounted for less than 2% of the administered dose. The major metabolites in both plasma and urine samples were 4'-O-beta-D-glucuronyl-4'-epidoxorubicin, 13-S-dihydro-4'-epidoxorubicin, and 4'-O-beta-D-glucuronyl-13-S-dihydro-4'-epidoxorubicin. This study demonstrates that a 135 mg/m2 bolus infusion given on a 3-weekly schedule is an appropriate initial dose for further clinical studies.

Biotransformation↗
PubMed1990

Granulocyte-macrophage colony stimulating factor from human lymphocytes. The effect of glycosylation on receptor binding and biological activity.

Native human granulocyte-macrophage colony stimulating factor (hGM-CSF) has previously been purified using methods which typically required several sequential chromatographic steps and only yielded small amounts of hGM-CSF. We have purified and characterized hGM-CSF using monoclonal antibodies raised against bacterially synthesized hGM-CSF. Activated donor T-lymphocytes grown in interleukin-2 and then reactivated with phytohemagglutinin produce several forms of hGM-CSF which can be purified using immunoaffinity absorption followed by reversed phase high performance liquid chromatography. The purified hGM-CSF consisted of at least nine species ranging in molecular weight (Mr) from 14,500 to 32,000. The higher Mr forms contained one or two N-linked carbohydrate moieties and were more acidic by two-dimensional Western blot analysis, consistent with increasing sialation. N-terminal sequence analysis of high and low molecular weight hGM-CSF fractions corresponded to that predicted by the cDNA sequence. Using the AML 193 [3H]thymidine incorporation assay the specific activity of the heavily glycosylated hGM-CSF was 1 x 10(8) units/mg compared with 6 x 10(8) units/mg for the non-glycosylated hGM-CSF produced by Escherichia coli. The different hGM-CSF forms induced neutrophil superoxide anion production by a variable amount depending on the extent of N-linked glycosylation. Receptor binding studies demonstrated lower receptor affinity for the heavily glycosylated form (KD = 820 pM) compared to less heavily glycosylated (KD = 78 pM) and non-glycosylated hGM-CSF produced by E. coli (KD = 30 pM). These differences are due to differences in the kinetic association rate.

Binding, Competitive↗
PubMed1990

The effects of dose and route of administration on the pharmacokinetics of granulocyte-macrophage colony-stimulating factor.

The pharmacokinetics of granulocyte-macrophage colony stimulating factor (GM-CSF) (0.3-30 micrograms/kg) were studied after subcutaneous bolus (n = 16) or intravenous bolus (n = 5) injection or 2 h intravenous infusion (n = 12). Each method of administration gave a different GM-CSF concentration-time profile. Highest peak serum concentrations (Cmax) followed the intravenous bolus, and the time GM-CSF persisted at a concentration greater than 1 ng/ml (t greater than 1 ng/ml) was longer after a subcutaneous than after an intravenous injection. Area under the concentration-time curve (AUC), Cmax and t greater than 1 ng/ml all increased with dose for each method of administration. After intravenous administration, there was a two-phase decline in concentration. The half-life (t1/2) of the terminal phase following an intravenous bolus ranged from 0.24 to 1.18 h and, following intravenous infusion, from 0.62 to 9.07 h and appeared to increase with dose. The apparent clearance was greatest following subcutaneous injection at doses below 3 micrograms/kg, suggesting a saturable mechanism or different bioavailability. Only 0.001%-0.2% of the injected dose appeared in the urine as immunoreactive GM-CSF.

Adult↗
PubMed1990

Monoclonal antibodies that recognize human granulocyte-macrophage colony-stimulating factor and neutralize its bioactivity in vitro.

We have produced monoclonal antibodies to bacterially synthesized, human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and have studied in detail the characteristics of three strongly neutralizing antibodies. The antibodies reacted with GM-CSF at high dilution (EC50 = 0.1-1.7 nM) in an indirect ELISA but did not react with murine GM-CSF or other cytokines. They also recognized glycosylated hGM-CSF produced by human lymphocytes. The antibodies were able to immunoprecipitate rhGM-CSF, but only reacted weakly with rhGM-CSF on Western blots, indicating that they recognized a conformation-dependent epitope. Cross-blocking studies showed that the three antibodies recognized overlapping epitopes. The antibodies inhibited binding of 125I-labeled rhGM-CSF to HL-60 cells at nanomolar concentrations and neutralized GM-CSF activity in two different bioassays. These antibodies thus provide a useful tool for analyzing the specificity of bioassays and for further studies of the production and function of GM-CSF in vitro and in vivo.

Animals↗
PubMed1990

Selective uptake of hematoporphyrin derivative into human cerebral glioma.

The uptake of hematoporphyrin derivative (HpD) into human cerebral glioma was measured using a porphyrin extraction technique. Patients with cerebral glioma were injected with HpD at a dose of 5 mg/kg body weight 24 hours before surgery and photoradiation therapy (PRT). Biopsies of tumor, and where possible, adjacent brain and normal brain were taken for analysis of HpD uptake. HpD was selectively localized into all grades of glioma, and there was a direct correlation between the grade of glioma and HpD level in the tumor. The levels were highest in glioblastoma multiforme (mean uptake of 5.9 micrograms of HpD/g of tumor wet weight) and lower in the intermediate-grade anaplastic astrocytoma (mean uptake of 2.4 micrograms/g of tumor) and the low-grade astrocytoma (1.6 micrograms/g of tumor). Uptake into normal brain tissue taken from HpD-sensitized patients was 0.2 microgram/g. HpD was also localized into the "brain adjacent to tumor" region. The selective uptake into the low-grade glioma suggests that PRT may be of use as an adjuvant therapy in these tumors and the detection of HpD in this region indicates that PRT may control the spread of tumor infiltrating into the adjacent normal brain.

Brain Neoplasms↗