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M Dowsett

Publications and source records attributed to M Dowsett.

At least 199 records · Page 11Linked to original sources
PubMed1991

Comparison of aromatase activity in human prostatic, testicular and placental tissues.

The aromatase enzyme was quantified by the release of tritiated water from [1 beta-3H] androstenedione. Tritiated water was released by the crude homogenates in 4 of 18 samples of benign prostatic hyperplasia tissue and one of 5 samples of prostate carcinoma tissue. However, this apparent aromatase activity was not inhibited by 4-hydroxyandrostenedione (0.5 and 5.0 microM), and none of the particulate fractions (100,000 g pellet) prepared from each of the prostatic tissues exhibited aromatase activity. Particulate fractions from rat ovary (n = 3) and human testes (n = 6) displayed significant aromatase activity (mean values of 9.9 and 0.033 nmol estrone formed/g protein/h, respectively). The testicular aromatase was inhibited by aminoglutethimide, 4-hydroxyandrostenedione and CGS 16949A with IC50 values of 6.4, 0.17 and 0.0017 microM, respectively. These are of a similar order to values obtained with the aromatase enzyme from human placental microsomes (14, 0.43 and 0.0075 microM, respectively).

Androstenedione↗
PubMed1991

Measurement of aromatisation by a urine technique suitable for the evaluation of aromatase inhibitors in vivo.

By modification of a recently developed method for separation of radio-labelled urinary oestrogens we were able to separate oestrogen metabolites and measure their isotope ratios in urine following injections of [3H]delta 4-androstenedione and [14C]oestrone. This method provides a useful tool for studying in vivo aromatisation of delta 4-androstenedione into oestrone in breast cancer patients before and during treatment with aromatase inhibitors.

Aminoglutethimide↗
PubMed1990

Clinical development of aromatase inhibitors for the treatment of breast and prostate cancer.

Numerous aromatase inhibitors are under development for breast cancer treatment. The major aims are to obtain a drug which at its dose of maximum efficacy has no effect on other endocrine systems, has no clinical side-effects and is convenient to administer. During the early clinical stages of development detailed endocrine and pharmacokinetic analyses are a valuable aid in the establishment of a drug's selectivity and its optimum dose, route and frequency of administration. The optimal dose may be defined as the minimum that will achieve maximal and sustained suppression of aromatase activity. This has generally been measured indirectly by comparing the suppression of plasma oestrogen levels at a selection of dosages. This approach has major advantages in speeding dose selection for therapeutic clinical trials. However, it also has some disadvantages including the unproven assumption that clinical response has a direct relationship with the degree of oestrogen suppression. In addition there are technical difficulties of analysis, of wide variability in endocrine response between patients and of demonstrating oestrogen suppression to be equivalent between doses (necessary to show maximal suppression). The direct measurement of aromatase inhibition in vivo by isotopic infusion analysis provides support to these indirect estimates. Its value is shown by our recent results with CGS16949A. The additional value of collating pharmacokinetic and endocrine measurements is apparent from our investigations of 4-hydroxyandrostenedione (4-OHA) and pyridoglutethimide. A consideration of our experience with these inhibitors may be helpful in directing the development of future agents. Whilst the value of aromatase inhibition in breast cancer is established its value in prostatic cancer is in doubt: we have found that 4-OHA is only poorly efficacious in advanced prostatic cancer.

Aminoglutethimide↗
PubMed1990

Aromatase inhibitors and hormone-dependent cancers.

Aromatase (estrogen synthetase) occurs in a variety of tissues. Using immunocytochemistry, we have recently located this enzyme in cellular compartments of several types of human tissue. Furthermore, we found the mRNA was located in the same structures where tested. As both gonadal and peripherally formed estrogen contribute to growth of hormone sensitive cancers, we have developed aromatase inhibitors to block synthesis of this hormone. We have determined that 4-hydroxyandrostenedione (4-OHA) selectively inhibits aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. 4-OHA was also found to inhibit gonadotropin levels and reduce estrogen and progesterone receptor levels in treated animals. The mechanism of these effects appear to be associated with the weak androgenic activity of the compound. These effects together with aromatase inhibition may result in a synergistic response reducing estrogen production and action. In postmenopausal women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either daily oral or parenteral weekly treatment with 4-OHA at doses that did not affect their gonadotropin levels, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occurred in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. These results indicate that 4-OHA is of benefit in postmenopausal patients with advanced disease who have relapsed from prior hormonal therapies, and that steroidal inhibitors may be of value in premenopausal patients.

Androstenedione↗
PubMed1990

Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A.

Thirty-one postmenopausal women with advanced breast cancer have been treated with the nonsteroidal competitive aromatase inhibitor CGS 16949A at p.o. doses of 0.3, 1, and 2 mg twice a day. All patients were assessed for response. Five patients, all treated with 1 mg twice daily, had objective evidence of response (two complete responses and three partial responses); disease stabilized in 17 patients. Minor side effects were reported by ten patients. Two further patients treated with 2 mg twice a day experienced persistent nausea which improved after dose reduction, and one patient, treated with 0.3 mg twice daily, developed a vasculitic rash requiring discontinuation of CGS 16949A. Estradiol levels measured in 24 patients were significantly suppressed 2 wk after starting CGS 16949A treatment at all doses used. Treatment with 2 mg twice a day lowered estradiol levels to a mean of 29% of pretreatment values which was significantly lower than the corresponding figure of 57% for patients treated with 0.3 mg twice daily. Aldosterone levels were significantly lowered below pretreatment values by the 1- and 2-mg twice daily doses. No clinically apparent cases of adrenocortical insufficiency occurred, although small changes in serum electrolyte levels were noted. The results indicate that CGS 16949A is an effective aromatase inhibitor, requiring further evaluation in the treatment of advanced breast cancer. The optimal dose is likely to be 1 mg twice a day.

Aldosterone↗
PubMed1990

Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men.

A study of the aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) was conducted in normal healthy men to compare the oral administration of two preparations of the drug: an unformulated, micronized powder and a formulated microcrystalline material (CGP 32349). The formulated material achieved a significantly higher mean peak concentration (88% greater than that obtained using the unformulated powder) and a higher mean AUC (not significant). The median time to peak was 1.5 h for both preparations and the elimination rate constants were similar (0.31 for micronized 4-OHA and 0.36 h-1 for formulated 4-OHA). Plasma concentrations of 4-OHA in this group were markedly lower than those previously observed in postmenopausal breast cancer patients. Significant biological activity was demonstrated with the formulated material in its suppression of plasma oestradiol levels, whereas no significant suppression was obtained using the micronized powder. An increase in androgen levels was observed that may have been due to competitive inhibition of enzymes involved in metabolic clearance of androgens and/or to decreased feedback inhibition of gonadotrophin secretion by oestradiol.

Adult↗
PubMed1990

Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione.

4-Hydroxyandrostenedione (4-OHA), a new specific aromatase inhibitor, was used to treat 57 postmenopausal women with advanced breast cancer at a dose of 250 mg by i.m. injection every 2 weeks; 55 women were assessable for response. In all, 18 patients (33%) had objective evidence of a response to treatment, with a median duration of 12 months; the disease stabilised in 8 (14%) patients. Serum oestradiol levels, which were measured weekly in nine of the patients, were found to be suppressed to a mean of between 36% and 51% of pretreatment levels during the first 6 weeks of treatment. Three patients were withdrawn from treatment because of toxicity (pain at injection site, sterile abscess and rash). One patient had an isolated episode of anaphylaxis after 6 months of treatment. In comparison with our previous reports of 4-OHA treatment, a dose of 250 mg given i.m. fortnightly appears to be the optimal dose regimen. The efficacy of the drug seems to be similar to that of tamoxifen and aminoglutethimide.

Adult↗
PubMed1990

Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer.

Inhibition of postmenopausal estrogen production by aromatase inhibitors is an established drug treatment modality for postmenopausal breast cancer. In this article postmenopausal estrogen disposition and the alterations caused by treatment with aromatase inhibitors are reviewed. Recent investigations have challenged the hypothesis that aromatization of androstenedione into estrone is the sole production pathway for estrogens in postmenopausal women. The finding that estrogens persist in the plasma of patients receiving aminoglutethimide treatment despite a near total inhibition of the aromatase enzyme suggests that alternative pathways for estrogen synthesis exist. While nonspecific actions of aromatase inhibitors may be disadvantageous, certain effects may also be beneficial. Recent findings that aminoglutethimide may induce estrone sulfate metabolism questions whether this "prototype" aromatase inhibitor might have a dual mechanism of action. The importance of investigating the possible influence of different aromatase inhibitors on all components of estrogen disposition is considered.

Aminoglutethimide↗
PubMed1990

Oestrogen receptor (ER) analysis in B-cell chronic lymphocytic leukemia: correlation of biochemical and immunocytochemical methods.

Oestrogen receptors (ER) are present in neoplastic lymphoid cells and have been considered a physiological marker of growth rate or differentiation. Tamoxifen, an oestrogen antagonist, has been given in some patients with CLL and Hodgkin's disease, with dramatic response in single cases. Until now, ER status has been assessed using a steroid binding assay (SBA) which has many inherent problems. Recently, the development of monoclonal antibodies directed against ER has been applied to the study of breast carcinomas and results obtained show good correlation with the quantitative SBA. We studied 49 cases of B-cell chronic lymphocytic leukemia (CLL) using immunostaining of cytospin preparations. In 30 of these cases ER enzyme immunoassay (ER-EIA) was also performed. Cultured MCF-7 cells, derived from a pleural effusion of a breast cancer patient, known to contain high levels of ER were used as a positive control (40-48% ER positive cells by immunocytochemistry; 200 fmol/mg protein by EIA). All of the CLL cases except two (96%) were negative for ER (less than 1% staining; less than 4 fmol/mg protein). The two positive cases expressed granular ER staining over the nucleus (9.2 and 12.1% positive cells) and were positive by EIA and SBA. It is concluded that (i) patients with CLL rarely express ER and (ii) immunocytochemical staining of cytospin preparations is a valid technique for the measurement of ER. It is of interest that one of the positive cases was diagnosed as CLL with Richter's transformation confirming earlier findings.

Adult↗
PubMed1990

Influence of superovulation on endometrial and embryonic development.

The authors have studied the temporal relationship between follicular rupture and endometrial development in 13 women during a natural ovarian cycle (length 25 to 35 days), and subsequently after standard treatment with clomiphene citrate, human menopausal gonadotropin and human chorionic gonadotropin (hCG) to induce multiple folliculogenesis for oocyte recovery, in vitro fertilization, and embryo freezing (cycle length 23 to 27 days). An endometrial biopsy was taken during both cycles 1.5 to 2.0 days after the oocytes had been released or removed. The samples were examined by light and transmission electron microscopy. Samples of peripheral blood were taken at defined times for hormone analysis. After treatment 11 subjects (85%) had advanced morphological development of the endometrium (8 women by 3 to 4 days, 3 women by 1 to 2 days). The concentrations of plasma estradiol (E2) and progesterone (P) on the days of follicular rupture and endometrial biopsy were significantly raised in the treatment cycles. The concentration of total urinary estrogens on the day of hCG administration and the mean change in the concentration of plasma E2 (treatment/control) on the days of endometrial biopsy were positively correlated with the extent of endometrial advancement. In addition, the mean change in the concentration of plasma P (treatment/control) was markedly increased on the days of follicular rupture and endometrial biopsy in those subjects with an advanced endometrium. Embryonic development was not so obviously related to the extent of superovulation. Asynchronous endometrial and embryonic development may therefore contribute to the low pregnancy rate in these patients.

Adult↗
PubMed1990

Aromatase inhibition in advanced prostatic cancer: preliminary communication.

We report the results of the first use of a steroidal aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA, CGP 32349), in the palliation of patients with advanced, hormone resistant, prostatic cancer. Twelve of 19 patients (63%), who had relapsed following castration and other therapies, gained significant pain relief following weekly intramuscular injections of 4-OHA. Five patients (31%) experienced a transient 'tumour flare', represented by an increase in bone pain soon after commencing treatment. The mechanism of action of 4-OHA in palliating patients with advanced prostatic cancer is obscure at present, but may represent an important new treatment modality which may lead to greater insight into prostatic biology.

Aged↗
PubMed1990

The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer.

The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.

Adult↗
PubMed1990

A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients.

Twelve premenopausal patients with advanced breast cancer were randomised to receive 3.75 or 7.5 mg of a slow release formulation of the luteinising hormone releasing hormone agonist leuprorelin once every 4 weeks. All patients were oestrogen receptor positive or unknown. Serum levels of gonadotrophins and oestrogens were suppressed markedly by both doses. All oestrogen values during treatment were within the postmenopausal range except for a single oestradiol level (274 pmol l-1) in one patient on the lower dose. There was no other indication that this lower dose was less effective as an oestrogen suppressant. There were two objective responders to the 3.75 mg dose and three to the 7.5 mg dose. Toxicity was confined almost entirely to hot flushes which occurred in 11/12 patients. We conclude that the slow release formulation of leuprorelin is effective in breast cancer treatment and that there is no major detriment to the use of the 3.75 rather than 7.5 mg dose.

Adult↗
PubMed1990

Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study.

We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.

Aged↗
PubMed1990

Potency and selectivity of the non-steroidal aromatase inhibitor CGS 16949A in postmenopausal breast cancer patients.

A selective inhibitor of aromatase is widely sought for the treatment of postmenopausal women with breast cancer. CGS 16949A has been shown to be a highly selective, potent inhibitor of aromatase in vitro. Its potency as an oestrogen suppressant and its selectivity were examined by treating 24 postmenopausal patients with advanced breast cancer for 4 weeks with doses of 0.3, 1.0 and 2.0 mg twice daily. The study was conducted in two parts which compared the two lower doses and the two higher doses separately in a cross-over design protocol. All doses significantly suppressed serum oestradiol and oestrone levels below pretreatment levels. Cross-over analysis indicated that the 2.0 mg twice daily dose achieved significantly greater suppression of oestradiol levels than 0.1 mg twice daily but there was no significant differences between any of the doses in the suppression of oestrone. No significant effects were noted on serum levels of LH, FSH, SHBG, prolactin, testosterone, androstenedione, 17-hydroxyprogesterone or cortisol. For the four steroids this was true both for basal samples and those collected after Synacthen stimulation. However, serum aldosterone levels were significantly suppressed by 1.0 mg twice daily CGS 16949A and further suppressed by 2.0 mg twice daily. It is concluded that CGS 16949A is a potent oestrogen suppressant in postmenopausal patients but that its effect is not totally selective.

Aged↗
PubMed1990

The effect of danazol and the LHRH agonist analogue goserelin (Zoladex) on the biological activity of luteinizing hormone in women with endometriosis.

In an attempt to determine whether the suppression in oestradiol levels caused by danazol is due to an effect on the hypothalamic-pituitary axis, we compared the endocrine effects of danazol with those of the LHRH (GnRH) agonist analogue goserelin. Serum levels of immunoreactive LH (I-LH), FSH, 17 beta-oestradiol (E2) and bioactive LH (B-LH) (using a mouse Leydig cell bioassay), were measured in ten and 20 women with endometriosis treated with danazol and goserelin, respectively. I-LH was measured both by radioimmunoassay (RIA) and immunoradiometric assay (IRMA). During 6 months of treatment with 600 mg of danazol daily, mean serum E2 decreased (P less than 0.05) to levels near the upper limit of the post-menopausal range (to a mean (and 95% confidence interval of the mean) of 117 (65-169) pmol/l) whereas FSH, I-LH (both by RIA and IRMA) and B-LH levels were not significantly altered. During 6 months of treatment with monthly depot injections of 3.6 mg goserelin, mean serum E2 decreased (P less than 0.001) to well within the post-menopausal range (to 23 (18-28) pmol/l). The mean FSH, I-LH and B-LH levels also decreased (P less than 0.05) during therapy with goserelin (from 3.9 (3.1-4.7) to 2.0 (1.6-2.4) IU/l for FSH, from 5.3 (4.5-6.1) to 1.9 (1.7-2.1) IU/l for RIA-LH, from 2.9 (2.5-3.3) to less than 0.5 (less than 0.5) IU/l for IRMA-LH and from 9.1 (7.1-11.1) to 2.9 (2.6-3.2) IU/l for B-LH).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Intratumoral aromatase as a prognostic factor in human breast carcinoma.

Intratumoral aromatase activity (AA) was measured in 145 samples of human primary breast carcinoma using the tritiated water release assay which quantifies the tritium lost to water during the aromatization of 1 beta-[3H]androstenedione to estrone. Significant AA was detected in 91/145 (63%) tumors. The possibility of a relationship between AA and a variety of clinical prognostic factors such as estrogen receptors, menopausal status, site, size, and histological grade of tumor was investigated. Possible relationship with time to relapse, overall survival, and survival of patients after relapse were also studied to determine whether intratumoral AA itself was of any prognostic value. There was no relationship between AA and tumor size, site, nodal status, menopausal status or estrogen receptors. However there was a significant correlation between AA and histological grade with an excess of AA-positive tumors having high grade (P = 0.03). There was no significant relationship between AA and overall survival (P greater than 0.1), but there was a marginal inverse correlation between AA and time to relapse (P less than 0.1). A statistically significant correlation was found between AA and survival of patients after relapse (P less than 0.05).

Aromatase↗