Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is a synthetic nonsteroidal drug with antiestrogenic properties. This report describes the response of patients with metastatic breast cancer to tamoxifen and correlates clinical responses with tumor tissue content of cytoplasmic estrogen binding proteins (EBPs) and other biochemical parameters. Ages of patients ranged from 27 to 82 years. 7 patients were premenopausal, 63 postmenopausal, and 2 had recent endocrine ablaetion. Prior hormone therapy, radiotherapy, or chemotherapy ahd been given to all patients. Tamoxifen was given at a dose of 20 mg orally for a minimum of 4 weeks and continued if an objective remission was shown. Before therapy a biopsy specimen was taken for determination of EBP and for specific enzyme activities. Another biopsy specimen was taken for at least 8 weeks after therapy. A total of 72 patients were treated for at least 4 weeks. The overall response rate was 38%. Most frequent responses were in the over-70 age group. The median duration of response has been 9.5 months. Bony involvement responded to therapy in 21 of 28 patients. No responses were shown in 6 patients with liver metastases. Only 1 of 18 patients who had previous chemotherapy responded. Of 31 who had no prior chemotherapy, 73% achieved a remission. There was a 44% correlation between patients with a positive EBP assay and response to therapy, but none in EBP-negative patients. In this study 20 of 28 patients had normal arylsulfatase B/DNA ratios in their tumor tissue and 11 of the 20 responded to tamoxifen therapy. Patients who responded most favorably to therapy had normal G-6-PD activities. It is concluded that tamoxifen therapy may cancel the need for ablative surgery in postmenopausal patients with positive EBPs and who have had a prior response to additive hormonal treatment.
 ...
PMID:Therapeutic use of tamoxifen in advanced breast cancer: correlation with biochemical parameters. 19 Nov 85

Despite the dramatic fall in plasma estrogen levels at menopause, only minor differences in breast tissue estrogen levels have been reported comparing pre- and postmenopausal women. Thus, postmenopausal breast tissue has the ability to maintain concentrations of estrone (E1) and estradiol (E2) that are 2-10- and 10-20-fold higher than the corresponding plasma estrogen levels. This finding may be explained by uptake of estrogens from the circulation and/or local estrogen production. Local aromatase activity in breast tissue seems to be of crucial importance for the local estrogen production in some patients while uptake from the circulation may be more important in other patients. Beside aromatase, breast tissue expresses estrogen sulfotransferase and sulfatase as well as dehydrogenase activity, allowing estrogen storage and release in the cells as well as conversions between estrone and estradiol. The activity of the enzyme network in breast cancer tissue is modified by a variety of factors like growth factors and cytokines. Aromatase inhibitors have been used for more than two decades in the treatment of postmenopausal metastatic breast cancer and are currently investigated in the adjuvant treatment and even prevention of breast cancer. Novel aromatase inhibitors and inactivators have been shown to suppress plasma estrogen levels effectively in postmenopausal breast cancer patients. However, knowledge about the influence of these drugs on estrogen levels in breast cancer tissue is limited. Using a novel HPLC-RIA method developed for the determination of breast tissue estrogen concentrations, we measured tissue E1, E2 and estrone sulfate (E1S) levels in postmenopausal breast cancer patients before and during treatment with anastrozole. Our findings revealed high breast tumor tissue estrogen concentrations that were effectively decreased by anastrozole. While E1S was the dominating estrogen fraction in the plasma, estradiol was the estrogen fraction with the highest concentration in tumor tissue. Moreover, plasma estrogen levels did not correlate with tissue estrogen concentrations. The overall experience with aromatase inhibitors and inactivators concerning their influences on breast tissue estrogen concentrations is summarized.
 ...
PMID:Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. 1462 18

Thirty years after the introduction of tamoxifen, which was expanded from palliation of metastatic cancer to recent application for chemoprevention, the primacy of this drug as the mainline pharmacological intervention is currently being challenged by the third generation aromatase inhibitors and inactivators. In contrast to the oestrogen receptor blockade provided by tamoxifen, aromatase inhibitors result in deprivation of oestrogens in postmenopausal women both through paracrine/intracrine and endocrine modulation. Experimental evidence has shown a significant (97-99%) reduction of in vivo aromatase activity and an equal or sometimes better antitumour activity compared with megestrol acetate when these drugs are used as second-line treatment for metastatic breast cancer. Recent pivotal studies in first-line settings comparing tamoxifen for metastatic breast cancer and preliminary results from the neoadjuvant trials demonstrate that third generation aromatase inhibitors are superior to tamoxifen. With a better understanding of local tissue production of oestrogen through oestrone sulfatase, which hydrolyses oestrone sulfate to oestrone, and 17-beta-hydroxysteroid dehydrogenase Type 1, which in turn catalyses the reduction of oestrone to oestradiol, more powerful tactics for oestrogen starvation of cancer may be realised in future.
 ...
PMID:Aromatase inhibitors and other novel agents in breast cancer treatment. 1598 53

Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women.
 ...
PMID:Steroid sulfatase: a new target for the endocrine therapy of breast cancer. 1747 Jun 79

Manipulation of the hormone oestrogen has been used for decades to treat hormone-dependent breast cancer. Currently, aromatase inhibitors (AIs) are used as first-line therapy against early and metastatic breast cancer in post-menopausal women. Despite these advances, several patients eventually experience a relapse of breast cancer and declined clinical response to treatment. As per recent findings, steroid sulfatase (STS) has emerged as a novel therapy target. This review aims at summarising the emerging field of STS inhibitor development and highlighting current findings from pre-clinical and clinical trials. The recently-developed dual-targeting compounds, such as dual aromatase-sulfatase inhibitors (DASI), have shown encouraging preclinical results and represent important new treatments for hormone-dependent breast cancer.
 ...
PMID:Steroid sulfatase inhibitors: promising new therapy for breast cancer. 2390 52