Biomedical subjects

M Dowsett

Publications and source records attributed to M Dowsett.

At least 163 records · Page 9Linked to original sources

PubMed1993

Effect of oestrogen receptor status and time on the intra-tumoural accumulation of tamoxifen and N-desmethyltamoxifen following short-term therapy in human primary breast cancer.

While the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyltamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intra-tumoural concentrations of TAM between ER-ve and ER+ve tumours was observed (717.9 +/- 166.4 ng/gm, and 518.6 +/- 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER-ve compared with ER+ve tumours (120.9 +/- 49.9 ng/gm and 450.1 +/- 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER-ve tumours (r = 0.72, p < 0.02), whereas for ER+ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER-ve tumours, but in ER+ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER-ve compared with ER+ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER+ve and ER-ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5-7 fold greater than serum. Unlike recent reports on acquired resistance, therefore, de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.

Aged↗

PubMed1993

Sex hormone binding globulin and non-protein-bound oestradiol in postmenopausal patients with primary biliary cirrhosis and normal controls.

Several studies have suggested that patients with primary biliary cirrhosis (PBC) have an increased risk of a number of medical conditions related to their oestrogen levels. This study has measured sex hormone binding globulin (SHBG) binding capacity, total oestradiol levels and percentage non-protein-bound (NPB) oestradiol and calculated the concentration of NPB oestradiol, in postmenopausal subjects in the following groups; normal controls, early PBC, advanced PBC and advanced PBC who were receiving therapy. Mean SHBG levels were higher in all groups of patients with PBC than in controls. No significant difference was observed in total or biologically active oestradiol between the four groups.

Aged↗

PubMed1993

Control of aromatase in breast cancer cells and its importance for tumor growth.

Three approaches have been taken to elucidate further the biological importance of intratumoural aromatase activity. (i) MCF7 and T47D hormone-dependent breast cancer cell lines both showed detectable aromatase activity in vitro. The up-regulation of this by TGF alpha indicates the possible existence of an autocrine growth stimulatory loop involving aromatase. (ii) Both tamoxifen and cytotoxic chemotherapy caused the suppression of aromatase activity in breast carcinomas in vivo. Aromatase activity prior to treatment did not predict for clinical response to tamoxifen. (iii) Transfection of aromatase into MCF7 cells led to their growth being stimulated by low doses of androgens and this was inhibited by the aromatase inhibitor CGS 16949A.

Aromatase↗

PubMed1993

Hormonal treatment of pancreatic carcinoma: a phase II study of LHRH agonist goserelin plus hydrocortisone.

Eighteen consecutive patients with measurable locally advanced or metastatic pancreatic adenocarcinoma were treated with goserelin (Zoladex) 3.6 mg subcutaneously every 4 weeks. Hydrocortisone 20 milligrams twice daily was commenced with the second injection of goserelin. Objective tumour response was monitored by computerised tomography of the abdomen. There was no objective remission in disease sites. Serial measurements of serum tumour markers showed no reduction in serum CA 19-9 and CA 195 concentrations. The median duration of survival of all cases was 5 months. Administration of goserelin resulted in significant reductions in oestradiol, testosterone, androstenedione in males and reductions in FSH and LH in both males and females. The addition of hydrocortisone resulted in further reductions of androstenedione and testosterone levels in males. Thus goserelin showed no anti-tumour effect, but concentrations required for direct inhibitory effects may be higher than those required to produce effects on hormone suppression.

Adenocarcinoma↗

PubMed1993

Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women.

We have performed a phase I study of the effect of a single dose of CGS 20267, an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg) or placebo separated by a washout period of at least 6 weeks. There was statistically significant suppression of serum estrone and estradiol at all three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary excretion of estrone and estradiol was also suppressed, although this did not reach statistical significance. Serum concentrations of aldosterone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH were unaffected by CGS 20267. The drug was well tolerated, with no significant side-effects. This study has shown CGS 20267 to be a potent and specific aromatase inhibitor, and further studies are now needed to assess its clinical efficacy.

17-alpha-Hydroxyprogesterone↗

PubMed1992

Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment.

We have investigated the ability of tamoxifen to regulate members of the transforming growth factor beta (TGF-beta) family in human breast cancers in vivo. Using immunohistochemical techniques, we find that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient. The induced TGF-beta is localized between and around stromal fibroblasts and appears to be derived from these cells. Lower levels of TGF-beta 1,-beta 2, and -beta 3 seen in epithelial cells were not altered by tamoxifen treatment. The increased stromal staining of TGF-beta 1 occurred in estrogen receptor-negative as well as estrogen receptor-positive tumors. These results provide in vivo evidence for a novel, estrogen receptor-independent mechanism of action for tamoxifen, involving the stromal induction of a potent growth inhibitor for epithelial cells.

Biomarkers, Tumor↗

PubMed1992

Steroid and growth factor modulation of aromatase activity in MCF7 and T47D breast carcinoma cell lines.

The effect of a number of steroids, growth factors, and peptides on aromatase activity in two estrogen receptor positive breast cancer cell lines (MCF7 and T47D) was investigated. The cells were incubated in Dulbecco's minimum essential medium containing phenol red and 10% fetal calf serum. Pronounced differences in basal aromatase activity and different responses to the addition of experimental agents were found in the two cell lines. Aromatase activity in MCF7 cells was significantly stimulated by phorbol 12,13-diacetate [PDA], dibutyryl cyclic AMP [(Bu)2cAMP], transforming growth factor alpha, and epidermal growth factor individually and PDA and (Bu)2cAMP in combination, while it was inhibited by dexamethasone and unaffected by transforming growth factor beta, fibroblast growth factor, platelet-derived growth factor, prolactin, and tamoxifen. Addition of cortisol to MCF7 cells had no effect on aromatase activity at 1 nM, caused suppression of activity at 10 nM and stimulated activity at 100 nM. Aromatase activity in T47D cells was stimulated by transforming growth factor alpha, epidermal growth factor, platelet-derived growth factor, prolactin, dexamethasone, and cortisol individually and PDA and (Bu)2cAMP in combination. It was unaffected by transforming growth factor beta, PDA, (Bu)2cAMP, and fibroblast growth factor. These findings suggest that aromatase activity is induced by agents which stimulate cyclic AMP-dependent protein kinases [e.g., (Bu)2cAMP] and that this effect is potentiated by factors which stimulate protein kinase C [e.g., PDA]. The effect on aromatase activity of growth factors, the actions of which are believed to be mediated by receptors linked to tyrosine kinase activity, is not as clearly defined, with a factor causing stimulation, inhibition, and no change in activity depending on the tissue concerned. Further insight into these differences will require resolution of the molecular mechanisms that mediate the actions of stimulatory and repressive growth factors on aromatase activity of oestrogen-producing cells.

Aromatase↗

PubMed1992

Influence of aminoglutethimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione treatment.

The clinical and biochemical effects of combined treatment with the two aromatase inhibitors aminoglutethimide and 4-hydroxyandrostenedione were evaluated in 10 patients suffering from advanced breast cancer. All patients had become resistant to treatment with one of the drugs before having combined treatment. Seven patients progressing on 4-hydroxyandrostenedione who had aminoglutethimide added to their treatment and achieved a further suppression of plasma oestradiol by a mean of 40.0% (p < 0.05). Plasma oestrone was suppressed by a mean of 40.6% (p < 0.025) and plasma oestrone sulphate was suppressed by a mean of 63.6% (p < 0.025). Two of the patients, neither of whom had responded to 4-hydroxyandrostenedione alone, experienced objective tumour regression when aminoglutethimide was given in concert. Three patients progressing on aminoglutethimide who had 4-hydroxyandrostenedione added showed no further suppression of their plasma oestrogen levels, and no tumour regression was observed. These findings suggest a dose-response relationship between plasma oestrogen suppression at low postmenopausal levels and objective tumour response in breast cancer.

Adult↗

PubMed1992

The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients.

The influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) given intramuscularly on the peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer and compared with the suppression of plasma oestradiol (E2). 7 patients were investigated before and during treatment on day 7, i.e. midway between two weekly injections. After an intravenous injection of [3H] androstenedione and [14C] oestrone, urine was collected for 96 h and the isotope ratio determined in the urinary oestrogen metabolites after isolation with high performance liquid chromatography. At 250 mg, 4OHA inhibited aromatisation to [mean (S.D.)] 15.2 (5)% of baseline (P < 0.002). There was significantly greater inhibition to 8.1 (2.7)% at 4OHA 500 mg (P < 0.01). Plasma E2 was reduced to 41.2 (14.1)% of baseline at 4OHA 250 mg with a further reduction to 32.7 (19.8)% at 500 mg (P < 0.05). These results confirm the dose-response relation previously established with plasma oestrogen measurements alone.

Aged↗

PubMed1992

4-hydroxyandrostenedione: a new treatment for postmenopausal patients with breast cancer.

We have evaluated 4-hydroxyandrostenedione, a specific inhibitor of aromatase, as treatment for breast cancer in a phase I dose-ranging study and a phase II study of the best-tolerated dose. 168 postmenopausal patients with locally advanced and metastatic breast cancer were treated intramuscularly. 19% of patients attained a complete or partial response but 26% of those who completed at least 4 weeks treatment responded. Side-effects were least in the group receiving 250 mg every 2 weeks. 13% of patients experienced local discomfort due to the injection and 5% had other side-effects. Serum oestradiol fell to 42.4 and 26.5% of baseline at 7 days after the start of treatment with the 250 mg and 500 mg dose, respectively. We conclude that 4-hydroxyandrostenedione at 250 mg every 2 weeks is a safe and effective form of treatment for postmenopausal patients with metastatic breast cancer.

Adult↗

PubMed1992

The effect of a low-fat diet on hormone levels in healthy pre- and postmenopausal women: relevance for breast cancer.

It has been postulated that differences in the levels of circulating hormones may be the explanation for the epidemiological link between per capita dietary fat intake and the incidence of breast cancer. We have investigated this possible relationship in 19 postmenopausal, and 18 premenopausal women who completed a 4-week period on a diet aiming to reduce fat intake to around 20% of total kilocalories. 7-day dietary records revealed a significant decrease in dietary fat intake in both the pre- and postmenopausal groups (from 37.2% of calories from fat to 23.2% and from 37.9 to 24.3%, respectively). There was a minor increase in the level of sex hormone-binding globulin, and a small decrease in prolactin in the postmenopausal group, which were of borderline significance. There were no significant changes in total oestradiol (E2), or non-protein-bound (free) E2 concentrations. In the premenopausal group there were no significant changes in any of the hormone levels investigated.

Adult↗

PubMed1992

Oestradiol synthesis from oestrone in malignant breast epithelial cells: studies on a high affinity, 80 kDa form of oestradiol dehydrogenase.

Previous studies have shown that in the breast there are multiple forms of the enzyme oestradiol dehydrogenase (E2DH), responsible for the interconversion of oestrone (E1) to oestradiol (E2). We have now re-examined oestrogen metabolism in the breast cancer cell lines (T47D and MCF-7) and have shown that steroids previously shown to inhibit the conversion of E1 to E2 in normal breast tissue failed to do so when added to growing monolayers of these malignant cells. In contrast to earlier estimates in normal breast tissues, the apparent Km for this conversion in monolayers of these malignant cells is shown here to be considerably lower, at around 50 nM. Cell free studies on these cell lines have revealed the presence of a high affinity (for E1) form of this enzyme of Mw approximately 80 kDa. The ability to detect this enzyme in soluble cell fractions appears to be critically dependent on buffer composition. Normal breast epithelial cells and adipose tissue appear to be devoid of this form of E2DH. As this form of E2DH has the highest affinity for the substrate E1 of all the forms in the breast, it is probable that this 80 kDa enzyme is responsible for the conversion of E1 to E2 in cell monolayers. If the observation holds that the 80 kDa enzyme is absent in the normal tissues, then the possibility arises that this E2DH may be linked with the neoplastic process in some breast tumours containing malignant epithelial cells of a similar type as studied here.

Adipose Tissue↗

PubMed1992

Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients.

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.

Androstenedione↗

PubMed1992

Aromatase activity, serum oestradiol and their correlation with demographic indices.

Peripheral aromatase activity was measured in 24 postmenopausal women suffering from advanced breast cancer. The % conversion of androstenedione to oestrone was then assessed for a significant correlation with age, weight, height, Quetelets index (weight/height2, Q.I.) and length of menopause. Serum oestradiol (E2) levels were measured in 22 of the subjects and compared with the same indices. There was no correlation between E2 or aromatase activity with the length of menopause (P = 0.3 and P = 0.5, respectively). In our data aromatase activity did not correlate with age (P greater than 0.5, n = 22). Serum E2 levels (P = 0.07, n = 20) expressed a negative correlation (i.e. decreased) with age. There was also a poor correlation between aromatase activity and weight of Quetelets index (P = 0.3, n = 20 for both). Serum E2 levels showed a statistically significant correlation with weight (P = 0.01, n = 21), but the relationship with Quetelets index just failed to attain statistical significance (P = 0.07, n = 20). In both cases the regression line was positive. When aromatase activity was correlated with serum E2 levels the regression line was positive but not statistically significant (P = 0.4, n = 22). The data indicate that aromatase activity is only one factor determining the differences in serum E2 levels between postmenopausal women.

Adult↗

PubMed1992

An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients.

43 postmenopausal breast cancer patients were treated orally with the aromatase inhibitor formestane (4-hydroxyandrostenedione) at daily doses of 62.5, 125, 250 or 500 mg for 4 weeks followed by 250 mg daily for a further 4 weeks. For some patients, 62.5 mg did not suppress serum oestradiol levels maximally. The doses of 250 and 500 mg did not differ in their effectiveness. Oestrone levels were suppressed by all doses of formestane but no consistent changes of aldosterone, cortisol or 17-hydroxyprogesterone occurred. Serum levels of sex hormone binding globulin fell by about 15% during treatment with 250 mg formestane reflecting its minor androgenic activity. The maximum concentration and area under the curve of serum formestane levels after the first dose varied in an approximately linear manner with dose. It is concluded that formestane is an effective, specific suppressant of oestradiol levels via the oral route requiring no more than 250 mg to be given daily.

Administration, Oral↗

PubMed1992

Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer.

We report the use of the steroidal aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA, CGP 32349), in the management of patients with advanced, hormone resistant, prostatic cancer. Eighteen of 25 patients (72%) showed a subjective response, mainly in the form of pain relief and increased performance. There were no objective improvements. A tumour flare occurred in 17/25 (68%). Detailed endocrine studies were performed during treatment. These showed that suppression of serum oestradiol levels occurred in 19/25 (76%) of patients during treatment with 4-OHA. Serum levels of androstenedione increased in 9/14 patients (64%). Concentration of serum testosterone and 5 alpha-dihydrotestosterone were elevated in 3/14 (21%) and 2/11 (18%) patients respectively. There appeared to be no correlation between response or tumour flare and changes in steroid levels during treatment with 4-OHA. The mechanism of action of 4-OHA in palliating patients with advanced prostatic cancer remains obscure. 4-OHA or its metabolites may be acting on metastatic bone metabolism via effects on oestrogen related osteoclastic and osteoblastic activity. Further investigation of the effects of aromatase inhibitors on prostatic biology, and bone metabolism in patients with metastatic prostate cancer, would appear worthwhile.

Aged↗

PubMed1992

The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer.

The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-14C]E1) and [6,7-3H] androstenedione ([6,7-3H]4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured. AG mean aromatase inhibition was 90.6% +/- 1.8 s.e.m. and E2 suppression 75.7% +/- 7.3 s.e.m. RG mean aromatase inhibition was 50.6% +/- 9.8 s.e.m. at 200 mg bd, 63.5% +/- 5.7 s.e.m. at 400 mg bd and 73.8% +/- 5.8 s.e.m. at 800 mg bd. E2 suppression was 30.7% +/- 9.5 s.e.m., 40.2% +/- 10.3 s.e.m. and 57.6% +/- 9.2 s.e.m. respectively. These results confirm the efficacy of AG as an aromatase inhibitor. RG produced dose dependent E2 suppression and aromatase inhibition, but even at the maximum tolerated dose of 800 mg bd had sub-optimal aromatase inhibition and oestradiol suppression compared with AG.

Adult↗

PubMed1992

A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.

Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer.

Aged↗