Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Clinical development of aromatase inhibitors for the treatment of breast and prostate cancer. 214 4

Estrogen deprivation by aromatase inhibition is an effective treatment in breast cancer. Between October 1986 and March 1988, 91 postmenopausal patients with advanced breast cancer entered a phase II study performed jointly in three center to investigate the new aromatase inhibitor 4-hydroxyandrostenedione. Patients received 500 mg 4-hydroxyandrostenedione intramuscularly (IM) every 2 weeks for 6 weeks, and 250 mg every 2 weeks thereafter. There were two complete (CRs) and 19 partial remissions (PRs) (response rate, 23%). Disease stabilization (no change; NC) was seen in 26 patients, and in 44 patients (48%), disease progression occurred. Duration of the CRs is 20+ months, median durations of PR and NC are 13+ and 8 months, respectively. Receptor status, relapse-free interval, and sites of metastatic lesions did not appear to influence treatment results. However, efficacy of previous tamoxifen treatment favorably predicted response to 4-hydroxyandrostenedione. Serum estradiol levels decreased significantly in patients after 2 weeks of treatment. Side effects were mostly nonspecific and of low degree, requiring discontinuation of treatment in only 3% of the patients. We conclude that aromatase inhibition with 4-hydroxyandrostenedione is efficacious in the treatment of postmenopausal breast cancer.
 ...
PMID:Aromatase inhibition with 4-hydroxyandrostenedione in the treatment of postmenopausal patients with advanced breast cancer: a phase II study. 218 41

Current status of endocrine treatment for breast cancer is reviewed. Several new aromatase inhibitors as well as antiestrogens are being introduced for clinical trials. As different drugs within the same drug group may possess different biochemical actions, apart from being useful drugs for treatment of breast cancer, these drugs may also extend our knowledge about the endocrinology of breast cancer.
 ...
PMID:New endocrine drugs for treatment of advanced breast cancer. 219 39

A mammalian cell expression plasmid, pH beta-Aro, containing the human placenta aromatase complementary DNA was constructed. The prepared plasmid was used to transfect breast cancer cells (MCF-7), noncancerous breast cells (HBL-100), and Chinese hamster ovary cells by a stable expression method. While the maximum velocities for aromatase expressed in three types of cells were different (10-201 pmol of [3H2O] formed/h/mg) using [1 beta, 2 beta-3H]androst-4-ene-3,17-dione as the substrate, the apparent Michaelis-Menten constants were found to be similar (39.9-57.8 nM) and were within the range determined for the enzyme existing in human placenta. The expressed activities were inhibited by the known aromatase inhibitors, 4-hydroxyandrostenedione and aminoglutethimide, at concentrations that normally inhibit the human placental aromatase. However, it was found that the inhibition profiles were different for aromatase expressed in different types of cells, suggesting that other factors, such as the uptake of the inhibitor, may also play a role in determining the inhibition efficiency. These constructed aromatase expressing mammalian cell lines will be very useful tools for aromatase inhibitor screening.
 ...
PMID:Stable expression of human aromatase complementary DNA in mammalian cells: a useful system for aromatase inhibitor screening. 220 60

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.
 ...
PMID:Aromatase inhibitors and hormone-dependent cancers. 225 37

Endocrine therapy is a major treatment modality for the systemic management of breast cancer. In comparison with alternatives such as chemotherapy, hormone manipulations have the advantage of lower toxicity but suffer from the disadvantages of producing responses in only 30-40% of patients with metastatic disease and seldom being curative. Nevertheless in recent years there have been significant advances in the endocrine treatment of breast cancer which have stemmed from a better understanding of the sources from which breast tumours may be supplied with hormones, the mechanism by which hormones regulate tumour proliferation and the more accurate identification of hormone sensitive tumours. As a result agents such as antioestrogens, aromatase inhibitors. LHRH agonists have largely superseded surgical and radiological ablation of endocrine organs. The major reduction in morbidity associated with these medical regimes means that they are much more acceptable to patients and may be used as adjuvants to local treatment of the breast in patients with "earlier" stages of the disease. At the same time patients can now be offered rational treatment selected on the basis of tumour biology rather than on more empirical criteria. The aims of this review are to provide details of the research which has led to this progress in endocrine treatment of breast cancer and to put into perspective the prospects for further advances.
 ...
PMID:Endocrine treatment for breast cancers: biological rationale and current progress. 227 30

Estrogens have an important role in the growth of breast and other hormone-sensitive cancers. We have shown that 4-hydroxyandrostenedione (4-OHA) selectively blocks estrogen synthesis by inhibiting aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. In postmenopausal men and women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either by daily oral or parenteral weekly treatment with 4-OHA, 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%. We recently studied the effects of 4-OHA and other aromatase inhibitors, 10-propargylestr-4-ene-3,17-dione (PED) and imidazo[1,5-alpha]3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile) (CGS 16949A) as well as 5 alpha-reductase inhibitors, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxyamide (4-MA) and 17 beta-hydroxy-4-aza-4-methyl-19norandrost-5-en-3-one (L651190) in prostatic tissue from 11 patients with prostatic cancer and six patients with benign prostatic hypertrophy (BPH), and from normal men at autopsy. We attempted to measure aromatase activity in tissue incubation by quantitating 3H2O released during aromatization of androstenedione or testosterone labeled at the C-1 position. The amount of 3H2O released from all samples was at least twice that of the heat inactivated tissue samples. The 3H2O release was significantly inhibited by 4-OHA and 4-MA, but not by the other aromatase inhibitors. However, when HPLC and TLC were used to isolate steroid products, no estrone or estradiol was detected in the incubates. Furthermore, no aromatase mRNA was detected following amplification by PCR. The 4-OHA was found to inhibit 5 alpha-reductase in both BPH and cancer tissue, although to a lesser extent than 4-MA. The other aromatase inhibitors were without effect. Although a mechanism involving intraprostatic aromatase is not likely, inhibitors may act to reduce peripherally-formed estrogens. In postmenopausal breast cancer, the results indicate that 4-OHA is of significant benefit.
 ...
PMID:Aromatase and other inhibitors in breast and prostatic cancer. 228 80

Aromatase activity has been measured in human breast cancers by incubating tumour minces with [7 alpha-3H]testosterone and characterizing purified oestradiol (E2) fractions by chemical derivative formation. Of 247 primary tumours, 178 showed evidence of oestrogen biosynthesis, levels varying between 0.5 and 12.5 fmol E2 produced/h/g tissue. These values were quantitatively small but at least comparable with those in other peripheral tissues. There was no correlation between presence or level of aromatase activity and the histopathology of the tumours although oestrogen biosynthesis was more likely to be present in more cellular tumours. Aromatase activity was also unrelated to age, menopausal status, lymph node status and T stage of the patient from which the tumour was derived. In a subgroup of patients presenting without clinical evidence of distant metastatic disease, no significant relation was detected between tumour aromatase and disease-free interval, but tumours without aromatase activity were associated with increased survival at 36 months after primary treatment. A statistically significant correlation was also detected between the presence of tumour aromatase and oestrogen receptors. Furthermore, in small subgroups of patients with "advanced" breast cancer tumour aromatase was related to response to aminoglutethimide but not tamoxifen therapy. Whilst these results do not conclusively define a role for local synthesis of oestrogen in the progression of breast cancer, this possibility still exists and further studies on tumour aromatase are warranted.
 ...
PMID:Relationship between tumour aromatase activity, tumour characteristics and response to therapy. 228 81

The effect of treatment with the aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA) on the peripheral conversion of androstenedione to estrone has been examined in eight postmenopausal women with advanced breast cancer. Before treatment conversion of androstenedione to estrone ([p]AEIBB) ranged from 0.81 to 3.7% and was almost completely inhibited after treatment with 4-OHA (two doses of 500 mg i.m. with an interval of 12 days between doses). Transfer constants were also measured by the urinary method ([p]AEIBU) for some subjects and decreased from 2.3 +/- 0.52% to 0.24 +/- 0.11% after treatment, a mean reduction of 90%. Mean plasma concentration of estradiol (37.4 +/- 16.6 pmol/liter) and estrone (99.0 +/- 32.2 pmol/liter) decreased significantly (P less than 0.01) to 15.7 +/- 4.6 pmol/liter and 52.4 +/- 8.9 pmol/liter, respectively, after treatment. Aromatase and DNA polymerase alpha (a marker of cell proliferation) activities were measured in seven samples of breast tumor tissue obtained before and after treatment. For three samples there was a marked (67 +/- 17%) decrease in tumor aromatase activity after treatment, for two, little change occurred, while tumor aromatase activity in the other two samples appeared to be resistant to the effect of 4-OHA. The correlation between tumor aromatase and DNA polymerase alpha activities (r = 0.45) failed to reach a significant level.
 ...
PMID:Effect of treatment with 4-hydroxyandrostenedione on the peripheral conversion of androstenedione to estrone and in vitro tumor aromatase activity in postmenopausal women with breast cancer. 229 55

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.
 ...
PMID:Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione. 232 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>