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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients. 138 47

To evaluate whether a tumour-directed gradient in androgen levels in fatty tissue can account for the maintenance of intra-tissue oestradiol levels, androstenedione (Adione), dehydroepiandrosterone (DHEA), testosterone (Testo) and androstenediol (Adiol) were assayed in breast tumour tissues and in fatty tissue taken at different distances from the tumour. The concentration of Adione was significantly lower in tumour tissue (5.6 +/- 1.5 pmol/g tissue; mean +/- SEM; n = 14) than in the adjacent fatty tissue (20.4 +/- 2.2; P less than 0.005). Testo, by contrast, occurred in equal concentrations in tumour (0.80 +/- 0.11) and in adjacent fatty tissue (0.70 +/- 0.07). Adione levels tended to be lower after the menopause only in fatty tissue, not in the tumour tissue; for Testo no differences were observed between samples from pre- and postmenopausal patients. Tumour DHEA levels (57 +/- 12 pmol/g tissue) were lower than those in fatty tissue (117 +/- 17; P less than 0.02). As with Adione, fatty tissue DHEA concentrations tended to be higher in pre- than in postmenopausal patients. Adiol showed a similar pattern as Testo. For none of the aromatase substrates nor their precursors a tumour-directed gradient was observed. The concentration of Adione in breast cancer tissue is much lower than the reported Km of the aromatase system for Adione. We have concluded, therefore, that the maintenance of oestradiol concentrations in tumour tissues is not substrate-driven.
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PMID:Tissue androgens and the endocrine autonomy of breast cancer. 138 49

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.
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PMID:The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients. 138 91

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5, 5, 12.5, 25, 50, 200, 400, and 800 mg (n = 3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35, 28, and 39% of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under the detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, all biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges.
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PMID:Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. 139 19

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.
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PMID:4-hydroxyandrostenedione: a new treatment for postmenopausal patients with breast cancer. 141 85

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.
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PMID:The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. 141 8

NADPH cytochrome c (P-450) reductase was purified from human placental microsomes using a combination of affinity and gel filtration chromatography. Affinity chromatography using agarose-hexane-adenosine 2'5 diphosphate resulted in two protein bands being detected by SDS-PAGE of approximate MwS 68 and 75 kDa. Fractions containing the two proteins were pooled, and then resolved using Sephacryl S-200. Both of the purified proteins displayed enzyme activity, measured by their ability to reduce cytochrome c. The 75 kDa protein obtained was used to immunize three female New Zealand white rabbits. The IgG fraction was partly purified from rabbit sera which suppressed placental microsomal NADPH cytochrome c reductase activity by > 80% using 33% ammonium sulphate. The procured antibody suppressed androstenedione aromatase activity in microsomal preparations of human placental and breast adipose tissue, and NADPH cytochrome c reductase activity in prostate (benign and malignant), MDA-MB-231 breast cancer cells, breast adipose, Hep G2 hepatoma cells and placental microsomal preparations. The extent of NADPH cytochrome c reductase inhibition varied in the order of malignant prostate < benign prostate < MDA < breast adipose < Hep G2 < placenta. The results suggest that human placental NADPH cytochrome c (P-450) reductase shares common antigenic epitopes pertinent to its capability of reducing cytochrome c in all of the above-mentioned tissues. In attempting to associate possible changes in NADPH cytochrome c reductase activity imposed by neoplasia to the obtained immunochemical cross reactivity and enzyme activity results, it was noted that microsomes obtained from MDA cells exhibited enzyme activity significantly less than that of breast adipose microsomes (1.6 and 8.1 nmol/min/mg protein, respectively) and by comparison showed 6% less homology towards the placental antibody. The results obtained for benign and malignant prostate showed no significant difference between the neoplastic states as adjudged by enzyme activity and immunochemical assays.
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PMID:Immunochemical specificity of placental NADPH cytochrome c (P-450) reductase in neoplastic and non-neoplastic human tissue. 141 86

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.
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PMID:Clinical breast cancer, new developments in selection and endocrine treatment of patients. 144 97

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.
Breast Cancer Res Treat 1992
PMID:Influence of aminoglutethimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione treatment. 144 52

The response of breast cancer to endocrine therapy depends on depriving the tumor cells of estrogen stimulation of cell division. This may be achieved by blocking estrogen synthesis in the body, using inhibitors of aromatase or by using drugs like tamoxifen, which interfere with the direct effects of estrogen on tumor cells. Current controversies relate to the mechanism for achieving more effective inhibition of estrogen synthesis and for the use of more specific antiestrogenic drugs.
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PMID:Current controversies in the endocrine therapy of advanced breast cancer. 146 21


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