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Biomedical subjects

J R Wilkinson

Publications and source records attributed to J R Wilkinson.

At least 19 recordsLinked to original sources
PubMed1991

4-Hydroxyandrostenedione in the prophylaxis of N-methyl-N-nitrosourea induced mammary tumourigenesis.

We have examined the role of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) in the prevention of mammary tumourigenesis in experiments involving 170 rats. We first demonstrated a prophylactic effect of 4-OHA (50 mg/week) in reducing tumour incidence over a 30 week period compared to controls (P = 0.04). We repeated the experiment to determine optimum dose and duration of therapy. Although 4-OHA again prevented tumour development (P less than 0.0005), there was no difference between the standard (50 mg/week) dose and the higher dose (100 mg/week). Rats were randomised at 30 weeks to either stop or to continue prophylactic therapy; marginal benefit in tumour free survival in continuing therapy was observed (P = 0.03). We conclude that 4-OHA is an effective agent in preventing carcinogen-induced mammary tumours in rats and further studies of the role of oestrogen synthesis inhibitors in the prevention of human mammary tumours may be indicated.

Androstenedione↗
PubMed1991

Effects of corticosteroids on cytokine generation and expression of activation antigens by monocytes in bronchial asthma.

The capacity of corticosteroids to inhibit the secretion of cytokines and the expression of selective antigens on monocytes has been studied in corticosteroid-sensitive (CS) and corticosteroid-resistant (CR) asthmatic patients. Incubation of monocytes derived from CS subjects with hydrocortisone inhibited the production of the enhancing activity, whereas in CR subjects hydrocortisone at concentrations of up to 10(-4) M did not suppress the release of enhancing activity. There was a rank order of potency for corticosteroid action: hydrocortisone less than methylprednisolone less than dexamethasone. The major activity was characterized as a heat-sensitive peptide of 3,000 daltons. The expression of CR1, CR3 and class II on asthmatic peripheral-blood mononuclear cells was increased relative to normal control donors. Culturing monocytes for 24 h in the presence of 10(-4) M hydrocortisone inhibited the expression of CR1, CR3 and class II in CS subjects but not in CR individuals. These results suggest that monocytes of CR asthmatic patients can increase the inflammatory potential of neutrophils and that they are hyperactive, as indicated by increased cytokine production and enhanced expression of activation markers, despite the presence of corticosteroids.

Adrenal Cortex Hormones↗
PubMed1991

Interactions of macrophages and monocytes with granulocytes in asthma.

The pathology of bronchial asthma demonstrates a multicellular process. The airway mucosa is infiltrated with both mononuclear cells and granulocytes, of which the eosinophil is particularly prominent. In an attempt to further the understanding of the interactions between different cells, we have elected to study the effects of monocyte/macrophage-derived cell products on granulocytes, because of the evidence for monocyte/macrophage activation in bronchial asthma.

Asthma↗
PubMed1990

Comparison of the generation of platelet-activating factor and leukotriene C4 in human eosinophils stimulated by unopsonized zymosan and by the calcium ionophore A23187: the effects of nedocromil sodium.

The generation of platelet-activating factor (PAF) and leukotriene C4 (LTC4) from normodense human eosinophils (EOSs), stimulated with unopsonized zymosan or calcium ionophore A23187, has been studied. There was a zymosan time- and dose-dependent increase in both PAF and LTC4 production. A plateau of 0.11 +/- 0.04 ng of PAF per 10(6) EOSs (mean +/- SEM; n = 7) and of 1.38 +/- 0.58 ng of LTC4 per 10(6) EOSs (n = 5) was reached at 5 x 10(8) zymosan particles at 37 degrees C for 30 minutes. Under optimal conditions, 91 +/- 1% of the PAF and 66 +/- 13% of the LTC4 remained cell associated. Calcium ionophore A23187 induced a time- and dose-dependent increase in the quantities of PAF and of LTC4 generated by EOSs. A plateau of 31 +/- 13 ng of LTC4 per 10(6) EOSs (n = 5) was reached at 1 mumol/L of calcium ionophore A23187 at 37 degrees C for 15 minutes. The dose response for PAF generation reached 4.2 +/- 0.8 ng/10(6) EOSs (n = 8) at 10 mumols/L of calcium ionophore A23187 at 37 degrees C for 15 minutes and had not plateaued; 90 +/- 5% of the generated PAF was cell associated. In vitro preincubation of EOSs with 10(-8) to 10(-4) mol/L of nedocromil sodium for 15 minutes did not change the subsequent generation or cellular distribution of PAF or LTC4 in EOSs optimally stimulated with either zymosan or calcium ionophore A23187.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Bronchial asthma is not associated with auto-antibodies to lipocortin-1.

Corticosteroids may mediate some of their anti-inflammatory action by the induction of lipocortin-1, which inhibits phospholipase A2 activity. Raised levels of antibodies to lipocortin have been found in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and it has been postulated that these may contribute to steroid resistance. A proportion of asthmatic patients fail to respond to treatment with corticosteroids and one possible mechanism is that these patients have raised levels of anti-lipocortin antibodies. We have therefore measured IgG and IgM antibodies to lipocortin by enzyme linked immunosorbent assay (ELISA) in eight corticosteroid-sensitive (CS) and 7 corticosteroid-resistant (CR) asthmatic subjects, and in eight normal controls. Comparison of asthmatic subjects with normal controls revealed no significant differences in either IgG or IgM antibodies to lipocortin. Comparison of CS asthmatic subjects with CR asthmatic subjects similarly revealed no significant differences in the concentration of either IgG or IgM antibodies to lipocortin. Levels of anti-lipocortin antibodies did not correlate with clinical response to treatment with 40 mg/day of prednisolone. Anti-lipocortin antibodies are unlikely to be involved in the inflammation seen in asthma, or in the relative insensitivity to corticosteroids seen in CR asthmatic subjects.

Adrenal Cortex Hormones↗
PubMed1989

Effects of monocyte- and macrophage-derived products on granulocyte function in asthma.

The pathology of bronchial asthma demonstrates a multicellular process. The airway mucosa is infiltrated with both mononuclear cells and granulocytes, of which the eosinophil is particularly prominent. In order to elucidate the cellular biology of airways inflammation, it is important to understand the interactions between different cells, as well as the biology of each individual cell type. The review highlights the effects of monocyte-macrophage-derived cell products on granulocyte function, because of the evidence for monocyte/macrophage activation in bronchial asthma.

Asthma↗
PubMed1989

Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma.

Peripheral blood mononuclear cells (PBMC) were isolated from seven normal subjects, eight asthmatic subjects clinically sensitive to corticosteroids (CS), and eight asthmatic subjects clinically resistant to corticosteroids (CR). PBMC were cultured at 37 degrees C for 24 h in the absence or presence of 10(-16) to 10(-4) M hydrocortisone. Calcium ionophore (A23187)-activated neutrophils (PMN) primed by supernatants of PBMC from asthmatic subjects cultured in the absence of hydrocortisone generated approximately threefold more leukotriene B4 than PMN primed by supernatants of PBMC from normal subjects (P less than 0.05). Incubation of PBMC derived from CS subjects with 10(-8) M hydrocortisone completely inhibited the production of the enhancing activity (P less than 0.01), whereas in CR subjects hydrocortisone at concentrations up to 10(-4) M did not suppress the release of enhancing activity. The enhancing activity was produced by monocytes. Enhancing activity eluted with an Mr of 3,000 D and a pI of 7.1. It eluted at 10% acetonitrile after reverse-phase HPLC. The activity was destroyed by heating to 60 degrees C for 60 min and was sensitive to pronase treatment. The purified factor also enhanced superoxide generation by PMN which had been stimulated submaximally by phorbol myristate acetate.

Adrenal Cortex Hormones↗
PubMed1986

Metabolism of the aromatase inhibitor 4-hydroxyandrostenedione in vivo. Identification of the glucuronide as a major urinary metabolite in patients and biliary metabolite in the rat.

4-Hydroxyandrost-4-ene-3,17-dione (HAD) is a potent and selective inhibitor of the enzyme complex aromatase, both in vitro and in vivo. The glucuronide is a major metabolite in the urine of patients and in the bile of rats given HAD and it was identified by chemical ionization-MS of the permethylated derivative. HAD glucuronide was quantified by first converting it enzymically into HAD, then determining HAD by capillary column GC-MS of the perfluorotolyl derivative using 4-hydroxyandrost-2,4-diene-3,17-dione as internal standard.

Androstenedione↗
PubMed1986

1,25-Dihydroxyvitamin D3 binding in estrogen-responsive rat breast tumor.

Receptors for 1,25 dihydroxyvitamin D3 [1,25-(OH)2D3] have been reported in breast tissue; however, the presence of multiple binding sites and limited availability of human tumor tissue have precluded complete biochemical characterization of the receptor in breast cancer. In the present study, binding proteins for 1,25-(OH)2D3 in breast tumor tissue were analyzed using a rat model of breast cancer. Breast tumors were induced in adult female rats with the carcinogen nitrosomethylurea. Such tumors previously have been shown to possess high levels of estrogen receptors and are estrogen dependent. Binding proteins for 1,25-(OH)2D3 in 0.3 M KCl extracts of tumor tissue were analyzed on sucrose density gradients. Two binding proteins were detected: one sedimenting at 5-6 S representing binding of 1,25-(OH)2D3 to the 25 hydroxyvitamin D3 (25OHD3) binding protein and a second moiety sedimenting, like the rat intestinal receptor, at 3.3 S. Binding of the dihydroxy metabolite to the faster sedimenting protein could be eliminated by inclusion of radioinert 25OHD3 in the incubation medium. Receptor content of rat breast tumor was investigated using an hydroxylapatite assay by incubating tumor extracts with a saturating concentration of 1,25-(OH)2-[3H]D3, plus unlabeled 25OHD3 to eliminate binding of the hormone to the 5-6 S species. Scatchard analysis of 1,25-(OH)2D3 binding to the tumor extracts yielded an apparent dissociation constant (Kd) of 0.33 nM. In summary, breast tumors induced in rats by nitrosomethylurea were shown to contain high affinity 1,25-(OH)2D3 receptors with properties very similar to those reported for the receptor in other mammalian target organs. The presence of receptors for 1,25-(OH)2D3 in these rat breast tumors implies that the tissue is potentially responsive to the hormone.

Animals↗
PubMed1986

Response of nitrosomethylurea-induced rat mammary tumor to endocrine therapy and comparison with clinical response.

We have compared the response of the N-methyl-N-nitrosourea-induced rat mammary tumor to various endocrine agents with response in patients with breast cancer. To do this, we have induced tumors in 228 animals (65% of intact rats developed tumors but only 14% of ovariectomized rats developed tumors). In intact rats, 4-hydroxyandrostenedione, tamoxifen, and a combination of tamoxifen, aminoglutethimide (AG), and danazol induced significant tumor regression (P less than 0.001, P = 0.01, P = 0.04, respectively), whereas danazol, AG, and trilostane were ineffective when used singly. Further investigation showed that the inactivity of AG in the rat was due to extensive acetylation of this compound. In order to mimic postmenopausal breast cancer, we ovariectomized rats after N-methyl-N-nitrosourea administration. In ovariectomized animals, AG was again ineffective in inducing tumor regression but 4-hydroxyandrostenedione was highly active when compared to controls (P = 0.002). Comparison with response of this model to endocrine therapy with response in patients indicates that this has good predictive capacity since it shows that agents which have minor activity in human breast cancer such as danazol and trilostane are inactive in the model. The intact rat model does not, however, predict whether a drug will be useful for pre- or postmenopausal patients. We recommend that before committing large numbers of patients to clinical trials on the basis of this model, the metabolism of new compounds should be compared in humans and rats.

Aminoglutethimide↗