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Biomedical subjects

M Dowsett

Publications and source records attributed to M Dowsett.

At least 181 records · Page 10Linked to original sources
PubMed1992

Towards a molecular basis for tamoxifen resistance in breast cancer.

Breast cancer patients who acquire tamoxifen resistance may respond to second-line hormonal therapy or progress to true endocrine resistance. The biological basis for these processes are poorly understood. Following successful therapy with tamoxifen there is little evidence at relapse for change in either the host endocrine environment or drug metabolic profile to account for the development of acquired resistance. Many tamoxifen resistant tumours still retain a structurally and functionally normal oestrogen receptor (ER) and yet will grow independent of oestrogen. The oestrogen-regulated molecular events which normally govern the growth of hormone-sensitive breast cancer involve a complex autocrine and paracrine interaction between several peptide growth factors (including TGF alpha, IGF-1 and TGF beta), their receptors and signal transduction pathways. Evidence now exists that constitutive activity of many of these mediators of the mitogenic signal can bypass the cell's dependence on oestrogen and provide a mechanism for hormone-independent growth. Research into these molecular mechanisms may result in a better understanding of how to overcome the clinical problem of tamoxifen resistance.

Breast Neoplasms↗
PubMed1992

Comparison of four immunochemical methods for the measurement of oestrogen receptor levels in breast cancer.

Four methods of assessing oestrogen receptor (ER) status were compared in 33 patients with operable primary breast cancer. The methods used to assess the ER status were immunocytochemical assay (ER-ICA) of frozen sections, fine needle aspirates and imprint material and enzyme immunoassay (ER-EIA) of tumour tissue. A mean overall ER positivity of 45% (15 out of 33), 41% (13 out of 32) and 21% (six out of 29) was obtained by immunocytochemical (ER-ICA) staining of frozen sections, fine needle aspirates and tumour imprints, respectively, and a mean overall ER positivity of 42% (14 out of 33) was obtained by ER-EIA. The concordance of ER positivity in pairs of data obtained from different method combinations was found to range between 72 and 91%. However, statistically there was no significant difference between the four methods on the basis of the data obtained. Good comparability has been shown between the three tissue analyses and therefore the method of choice is technically not immediately apparent.

Biopsy, Needle↗
PubMed1992

Effects of 4-hydroxyandrost-4-ene-3,17-dione and its metabolites on 5 alpha-reductase activity and the androgen receptor.

The steroidal aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione (4OHA) and its metabolites, 4-hydroxytestosterone (4OHT), 3 beta,17-dihydroxy-5 alpha-androstan-4-one (metabolite A) and 3 alpha, 17-dihydroxy-5 beta-androstan-4-one (metabolite B) were evaluated as inhibitors of the human prostatic 5 alpha-reductase enzyme and for binding to the rat prostatic androgen receptor. 4OHA and 4OHT were weak inhibitors of 5 alpha-reductase with IC50 values of 15-29 microM. Metabolites A and B had no significant inhibitory activity. 4OHA and metabolites A and B bound weakly to the androgen receptor. The binding affinities (RBA) relative to mibolerone (RBA = 100) were 0.085, 0.485 and 0.016, respectively. However, 4OHT (RBA = 75) was a more potent binder than the endogenous androgen 5 alpha-dihydrotestosterone (RBA = 66). The ability of these metabolites, in particular 4OHT, to bind to the androgen receptor may explain the in vivo androgenic activity of 4OHA.

5-alpha Reductase Inhibitors↗
PubMed1992

Clinical and endocrine effects of leuprorelin acetate in pre- and postmenopausal patients with advanced breast cancer.

Premenopausal Study. Twenty-five pre- or perimenopausal patients with advanced breast cancer were treated with leuprorelin acetate 3.75 mg (n = 9) or 7.5 mg (n = 16) every 4 weeks. Serum levels of gonadotrophins and oestrogens were suppressed markedly by both doses and there was no indication that the lower dose was less effective as an oestrogen suppressant. There were four objective responders to the 3.75 mg dose and six to the 7.5 mg dose. Toxicity was confined almost entirely to hot flushes, which occurred in 17 patients. Leuprorelin acetate is therefore an effective agent in the treatment of premenopausal breast cancer patients. There appears to be no major detriment to the use of 3.75 mg rather than the 7.5 mg dose. Postmenopausal Study. Fifteen postmenopausal patients with advanced breast cancer were treated with monthly injections of leuprorelin acetate 7.5 mg to assess the clinical activity and endocrine responses to treatment. None of the 15 patients showed an objective response to treatment, although four patients had stable disease for at least 6 months. Endocrine effects after 4 weeks' treatment included major suppression of serum gonadotrophins to below 10% of pretreatment values and decreases in the level of serum testosterone in 12 of 14 patients. In this group there were no changes in oestradiol levels, although we had previously observed suppression in postmenopausal patients treated with goserelin. In common with other gonadotrophin-releasing hormone analogues, leuprorelin acetate cannot be recommended as a treatment for postmenopausal breast cancer.

Adult↗
PubMed1991

Pyrrolidino-4-iodotamoxifen and 4-iodotamoxifen, new analogues of the antiestrogen tamoxifen for the treatment of breast cancer.

New tamoxifen analogues were tested for their antiproliferative activity both in vitro and in vivo. Binding studies showed that both 4-iodotamoxifen and pyrrolidino-4-iodotamoxifen and 2.5-fold higher affinities for the estrogen receptor compared with tamoxifen. Pyrrolidino-4-iodotamoxifen was also 1.5-fold more effective in causing inhibition of estrogen-induced growth of MCF-7 cells compared with tamoxifen at 10(-6) M. The 4-iodotamoxifen analogue was similar to tamoxifen in its inhibitory action at 10(-6) M. Antiproliferative activities of these drugs were tested using the nitrosomethylurea-induced rat mammary tumor model. Pyrrolidino-4-iodotamoxifen caused regression in 92% of rats, whereas tamoxifen caused regression in 75% of rats. The agonist activity of the analogues was determined using the immature rat and mouse uterotrophic assays. Both tamoxifen and 4-iodotamoxifen had similar partial agonist activity, and this was greater than that seen with pyrrolidino-4-iodotamoxifen. Furthermore, pyrrolidino-4-iodotamoxifen caused a dose-dependent inhibition of estrogen-induced vaginal cornification, whereas tamoxifen and 4-iodotamoxifen did not. These studies demonstrate that pyrrolidino-4-iodotamoxifen is more effective than tamoxifen in inhibiting tumor regression and that its reduced uterotrophic activity and increased estrogen receptor binding may give it significant clinical advantages over the parent compound.

Animals↗
PubMed1991

Determination of 4-hydroxyandrost-4-ene-3,17-dione metabolism in breast cancer patients using high-performance liquid chromatography-mass spectrometry.

A sensitive procedure for studying the metabolism of the steroidal aromatase inhibitor 4-hydroxy-androst-4-ene-3,17-dione (4OHA) was developed based on enzyme hydrolysis, liquid-liquid extraction and reversed-phase liquid chromatography coupled with a mass spectrometer (LC-MS) using a thermospray interface. Seven metabolites were identified from the hydrolysed urine samples together with the parent drug. The major routes of metabolism were via dehydrogenation, reduction of the ketone functional groups, reduction at the C-4-C-5 double bond and hydroxylation at the C-5 position. Confirmation of the identity of 4OHA and its metabolites isolated from female patients' urine samples was accomplished by comparison of the retention times of their corresponding synthetic standards on LC-MS. We have demonstrated that this technique is particularly suitable for studying the metabolism of steroidal drugs.

Administration, Oral↗
PubMed1991

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer.

The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3-4 days, oestradiol levels fell to 31.1% +/- 6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 micrograms/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates for Co (21.7 +/- 1.82 micrograms/ml), Km (2.66 +/- 0.68 micrograms/ml) and Vmax (0.86 +/- 0.06 micrograms ml-1 h-1). On subsequent repeated dosing with PyG, both the Km (4.31 +/- 0.48 micrograms/ml) and the Vmax (1.83 +/- 0.13 micrograms ml-1 h-1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.

Aminoglutethimide↗
PubMed1991

Low-dose aminoglutethimide in postmenopausal breast cancer: effects on adrenal and thyroid hormone secretion.

Aminoglutethimide is effective in the treatment of breast cancer in postmenopausal patients as a result of its inhibition of aromatase. Its use is complicated by a number of endocrine side-effects which include the inhibition of thyroxine synthesis and inhibition of 11-steroid and 21-steroid hydroxylases. When aminoglutethimide is used at the conventional daily dose of 1000 mg in combination with 40 mg of hydrocortisone these effects can result in clinically significant hypothyroidism and increases in the serum levels of oestrone in response to stimulation of adrenocorticotropic hormone (ACTH). In the current study it was found that with twice daily treatment at the low dose of 125 mg aminoglutethimide plus 20 mg hydrocortisone there was no significant increase in oestrone levels after ACTH stimulation. In addition there was little effect on thyroid function: serum levels of triiodothyronine and thyroxine were unaffected whilst there was a marginally significant (P less than 0.05) increase in thyroid-levels were confined to those patients with pretreatment values greater than 2.5 mU/L, the most marked effect being in 1 patient whose pretreatment level was already outside the normal range.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Albumin-bound and non-protein-bound oestradiol and testosterone in postmenopausal breast disease.

Several studies have recently reported the percentage of non-protein-bound (NPB) oestradiol (E2) to be higher in patients with breast cancer than in normal controls. Using postmenopausal volunteers, we have examined the fractional binding of E2 and testosterone (T), as well as total E2 and T, sex-hormone binding globulin (SHBG), luteinising hormone (LH) and follicle stimulating hormone (FSH), in normal women, those at risk of developing breast cancer and women with breast cancer at first diagnosis and first recurrence. No significant differences were observed in either the concentration or in the percentage of NPB E2 or T, or in any of the other hormones measured. The validity of our observations were confirmed by expected relationships between E2, T, SHBG and body mass.

Breast Neoplasms↗
PubMed1991

Inhibitors of steroidogenic enzymes for the treatment of breast cancer.

The most important mitogen for human breast cancer is oestrogen. Since oestrogens are synthesized via a protracted series of enzymic conversions from cholesterol, there are many potential targets for inhibition which could theoretically lead to suppression of oestrogen synthesis. However, inhibition of many of these targets is complicated by a resultant interference in the synthesis of other steroids, particularly glucocorticoids. This results in inhibitors of aromatase being the most rational choice for oestrogen suppression in breast cancer patients. Several aromatase inhibitors are in clinical usage. It is important that the clinical effectiveness of these is compared with that of the antioestrogen, tamoxifen.

Antineoplastic Agents↗
PubMed1991

The effect of the aromatase inhibitor, rogletimide (pyridoglutethimide), on guinea pig adrenal cell steroidogenesis and placental microsomal aromatase activity: comparison with aminoglutethimide and CGS 16949A.

A dispersed guinea pig adrenal system has been used to study the effect of the aromatase inhibitor rogletimide (RGL) on adrenal steroidogenesis. The ACTH-stimulated release of cortisol, 17-hydroxyprogesterone (17-OHP) and androstenedione (A) was measured following exposure of adrenal cells to RGL, or the other aromatase inhibitors aminoglutethimide (AG) and CGS 16949A. RGL at concentrations sufficient to cause 80-90% inhibition of placental microsomal aromatase had no effect on the release of all three steroids. In contrast, AG at 10(-5) M markedly reduced the output of all three steroids from these cells. CGS 16949A at 10(-6) M reduced the output of cortisol and increased the concentration of 17-OHP and A. These results indicate that RGL is unlikely to cause the suppression of cortisol synthesis which has been noted to occur with AG and CGS 16949A during the treatment of breast cancer patients.

Adrenal Glands↗
PubMed1991

The effect of danazol on pulsatile gonadotropin secretion in women with endometriosis.

OBJECTIVE: To determine whether the effect of danazol on gonadotropin pulsatility was due to a direct effect of the drug or the suppression in the estradiol (E2) levels. DESIGN: Prospective analysis of serial blood samples at 10-minute intervals for 5 hours on days 3, 4, or 5 of the control cycle and 2 months after the start of danazol treatment. SETTING: Tertiary institutional outpatient care. PATIENTS, PARTICIPANTS: Six eugonadal women with minimal endometriosis. INTERVENTIONS: Oral administration of danazol, 200 mg three times daily. MAIN OUTCOME MEASURES: Gonadotropin mean levels, pulse frequency, and amplitude. RESULTS: The mean level of E2 was the same in the control cycle as that during danazol treatment (170 pmol/L). Danazol administration resulted in a 16% increase in the mean luteinizing hormone (LH) pulse amplitude (95% confidence interval [CI] 6% to 26%, P less than 0.01), associated with a 20% decrease in LH pulse frequency (95% CI -71% to +31%, P = 0.37). There was a nonsignificant increase in follicle-stimulating hormone (FSH) pulse amplitude (2%, 95% CI -9% to +14%, P = 0.68) and in FSH pulse frequency (27%, 95% CI -4% to +58%, P = 0.08). The 22% decrease in the mean LH level (95% CI -85% to +12%, P = 0.13) and the 20% decrease in the mean FSH level (95% CI -53% to +37%, P = 0.33) were also not significant. CONCLUSIONS: The increase in LH pulse amplitude represents a direct effect of danazol on the hypothalamic-pituitary axis.

Adult↗
PubMed1991

The influence of CGS 16949A on peripheral aromatisation in breast cancer patients.

The influence of a new aromatase inhibitor, CGS 16949A on peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer. A mixture of 3H androstenedione and 14C oestrone was injected, and all urine was collected for the following 96 h. The isotope ratio was determined in the urinary oestrogen metabolites after isolation by HPLC. Eight patients were investigated before and during treatment with CGS 16949A. At a dose of 1 mg b.d. (eight patients) CGS 16949A inhibited aromatisation by a mean value of 82.4% (range 71.3 to 93.7%). When the drug dose was escalated to 2 mg b.d. (three patients) aromatisation was inhibited by a mean of 92.6% (range 90.6 to 95.8%), these results suggest that CGS 16949A at a dose of 1 mg b.d. causes submaximal aromatase inhibition in many patients, while a dose of 2 mg b.d. seems to result in greater than 90% aromatase inhibition. These data are consistent with previous observations that the higher dose is more effective in suppression of plasma oestradiol levels.

Aged↗
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

Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients.

The aromatase inhibitor, 'pyridoglutethimide' (PyG), has been shown previously to suppress serum oestrogen levels in postmenopausal breast cancer patients and to achieve clinical responses at a dose of 500 mg twice daily (b.d.). This report gives the results of a detailed pharmacokinetic and endocrine study of PyG in ten patients. Four doses were tested at intervals of 2 weeks in the following order: 200 mg b.d., 400 mg b.d., 800 mg b.d., 1200 mg b.d. Concentration-time profiles of serum levels of PyG were curvilinear in all patients probably reflecting a saturation of metabolic enzymes. During repeat-dosing metabolism was enhanced approximately 2-fold. Plasma levels of oestradiol were significantly suppressed by the lowest dose of PyG. Although higher doses appeared to achieve greater suppression this was not statistically significant in this small group of patients. There were no significant effects at any dose on the serum levels of cortisol, aldosterone, luteinising hormone, follicle stimulating hormone, prolactin, sex hormone binding globulin or thyroid stimulating hormone. There was a dose-related increase in 17 alpha-hydroxyprogesterone levels and a dose-related decrease in levels of dehydroepiandrosterone sulphate (DHAS). The androgens DHA, testosterone and androstenedione also were significantly suppressed with at least one of the doses of PyG. Synacthen tests did not support these changes being a result of inhibition of 17,20 lyase. It is possible that they are due to enhanced clearance of DHAS. Two patients experienced no toxicity throughout the study, whilst a total of four patients were withdrawn because of side-effects: one at 400 mg b.d., two at 800 mg b.d., and one at 1200 mg b.d. The most frequent side-effects were nausea and lethargy. One patient showed an objective response to treatment.

Aged↗
PubMed1991

Effects of cytotoxic chemotherapy on ovarian and adrenal steroidogenesis in pre-menopausal breast cancer patients.

Many patients on cytotoxic chemotherapy show reduced frequency of menstrual bleeding due to a reduction in ovarian follicular activity. The endocrine perturbations related to these changed menstrual patterns were studied in detail. Nineteen regularly menstruating patients with primary breast cancer were given either cyclophosphamide or chlorambucil in combination with methotrexate and fluorouracil as adjuvant therapy. Some patients continued to menstruate normally, while others became amenorrhoeic. However, the majority showed reduced menstrual activity, and, in these, the reproductive endocrinology was highly variable. Increased gonadotrophin levels brought about episodes of follicular activity but not ovulation. During these episodes, oestradiol levels reached normal follicular values. Adrenal function appeared to be unaffected. Although an endocrine response by the tumour might be expected to cytotoxic-induced ovarian ablation, the clinical significance of the disrupted, but incompletely suppressed ovarian function, is unknown.

Acetone↗