Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Aromatase inhibitor development for treatment of breast cancer. 774 29

The high serum concentration of estrone sulfate and the presence of estrone sulfatase in breast tumors constitute an important mechanism of local synthesis of estrogens in the tissue. Thus, inhibitors of estrone sulfatase may be effective in the treatment of estrogen-dependent breast cancer. In this study, we synthesized several isostructural analogs of estrone sulfate (estrone-3-methylsulfonate, estrone phosphate, 3-desoxyestradiol-3-methylenesulfonate, and 3-desoxyestrone-3-methylenesulfonate) and tested them on human placental sterylsulfatase. The results were (i) The Ki of 3-desoxyestrone-3-methylenesulfonate 12 and 3-desoxyestradiol-3-methylenesulfonate 7 are more than 100-fold higher than the Ki or KM values for estrone sulfate, (ii) As compared to estrone sulfate, the Ki value for estrone-3-methylsulfonate 2 is about 30-fold higher, while estrone phosphate 3 is bound by the sulfatase with roughly the same affinity as estrone sulfate. The results shed some light on the electronical and sterical requirements for high affinity binding to the enzyme.
...
PMID:Estrone sulfate analogs as estrone sulfatase inhibitors. 779 36

The synthesis and biochemical evaluation of estrone sulfatase inhibitors are described. Inhibitors were designed through modifications of the substrate estrone sulfate. An in vitro assay using the microsomal fraction isolated from human term placenta was used to evaluate sulfatase inhibitory activity. All the inhibitors (except sulfonyl chloride analog) exhibited low inhibitory activities in the screening assay. Sulfonyl chloride analog is a strong inhibitor, which caused 91.5% inhibition of the enzymatic activity at 300 microM.
...
PMID:Synthesis and biochemical studies of estrone sulfatase inhibitors. 847 13

Estradiol levels in breast tumors from post-menopausal women are similar to those in pre-menopausal women even though plasma estrogens are much lower after the menopause. In situ estrogen production by the tumor provides a potential means of maintaining high estradiol levels in post-menopausal breast cancer tissue. The estrone sulfatase pathway has been proposed as the mediator of in situ estrogen production. A number of studies suggest that estrone sulfate may be converted into estradiol in breast tumors via the catalytic activity of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase. However, these studies used pharmacologic levels of estrogen sulfates and have not shown that physiologic levels can support biologic effects. Accordingly, the present study examined the dose relationship of estrone sulfate to a variety of biologic endpoints in MCF-7 breast cancer cells in culture. These cells converted physiologic concentrations of estrone sulfate to quantities of free estradiol capable of stimulating cell growth. Under these conditions, the nuclear steroids observed were free estrone and estradiol. Increase in cell number after 6 days of exposure to steroid required 100 nM estrone sulfate. However, S-phase, a more sensitive measure of cell proliferation, was stimulated by 0.1 nM estrone sulfate, a clearly physiologic concentration. Stimulation of estrogen-dependent protein markers such as pS2 and progesterone receptor required much higher concentrations of estrone sulfate. These effects were mediated through the estrogen receptor since the pure anti-estrogen, ICI 164384, blocked all effects produced by estrone sulfate. While it has been suggested that anti-estrogens may partly exert their effects by inhibition of sulfatase and 17 beta-hydroxysteroid dehydrogenase, this did not occur under our experimental conditions. These data provide evidence of the relevance of the estrone sulfatase pathway since biologic effects can be demonstrated in response to physiologic concentrations of estrone sulfate.
...
PMID:Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF-7 cell cultures. 847 38

Steroid sulfatase (STS) is a single enzyme with a range of substrate specificities, including estrone sulfate. Using a 2.4 kb cDNA clone, expression of human STS was undetectable by Northern hybridization, but STS RNA was detected in human placenta, human breast cancer samples, and in breast carcinoma cell lines following reverse transcriptase-PCR amplification, using specific primers to yield a product of 472 bp. In preliminary studies, stimulation of MCF-7 cell lines with estradiol (10(-8) M) resulted in an increased level of amplifiable STS RNA, and this upregulation of STS RNA could be abolished by tamoxifen. The estrone sulfatase activity in mammary tumors derived from N-nitrosomethylurea (NMU) treated rats was significantly decreased in animals treated with tamoxifen compared to control animals, regardless of the response of the tumors to the antiestrogen (P < 0.05). Although tamoxifen does not inhibit the estrone sulfatase enzyme in vitro, it may modulate the expression of STS RNA and the enzyme activity in vivo.
...
PMID:Detection of breast cancer-associated estrone sulfatase in breast cancer biopsies and cell lines using polymerase chain reaction. 866 67

Estrone sulfatase is an important enzyme which catalyzes the production of estrone from estrone sulfate in a variety of human and animal tissues. We report, for the first time, on the presence of estrone sulfatase activity in thrombocytes from human blood. Incubation of [3H]estrone sulfate in the presence of human thrombocyte lysates resulted in the formation of [3H]estrone as assessed by two-dimensional TLC. Estrone sulfatase activity was localized in the mitochondrial-microsomal fraction in thrombocytes from human blood. The enzyme was thermostable and had an optimum pH of 5.60 in acetate buffer. The highest activity was obtained in the presence of 0.1% of either Nonidet P-40 or Triton X-100. Phosphate ions (1 mM) inhibited the enzyme activity by 64% and similar effects were observed in the presence of platelet-free plasma. Endogenous inhibitors had no effect on the observed enzyme activity under assay conditions as evidenced in this study. The apparent Km value was 3.16 +/- 0.08 microM for [3H]estrone sulfate and V was 188.5 +/- 2.6 (mean +/- SEM, n = 22) pmol.mg protein-1.h-1. Comparison between two thrombocyte preparative procedures provided evidence that thrombocyte estrone sulfatase activity should be measured in thrombocyte samples representing the whole thrombocyte population. This parameter appeared critical for accurate measurements of enzyme activity. The presence of estrone sulfatase activity in human thrombocytes provides a new non-invasive tool for the study of this activity both in physiological and pathological conditions which could be of potential clinical relevance.
...
PMID:Characterization of estrone sulfatase activity in human thrombocytes. 866 70

About one-third of breast cancers are classified as estrogen-dependent breast cancers. In the past 10 years, numerous reports have suggested the importance of estrone sulfate and estrone sulfatase in regulating the supply of estrogens to these cancers. Estrone sulfatase inhibitors may thus prove to be useful for the treatment of these diseases. Several research groups have reported the development of estrone sulfatase inhibitors, and estrone-3-O-sulfamate has been shown to be the most potent sulfatase inhibitor. However, a recent report indicated that estrone may be released during the inactivation of sulfatase by estrone-3-O-sulfamate and rendered the inhibitor to be estrogenic. Therefore, there is a need for a potent non-steroidal sulfatase inhibitor that is metabolically stable, more selective, and lacking estrogenic activity. We developed a series of (p-O-sulfamoyl)-N-alkanoyl tyramines, and they proved to be potent estrone sulfatase inhibitors. Using human placental microsome as the enzyme source, the best inhibitor in this series, compound 18, has an IC50 of 55.8 nM. Another potent inhibitor in this series, compound 17, exhibited time-dependent inactivation of sulfatase when incubated at various concentrations (0.2-1.0 microM) of the inhibitor. Estrone sulfate partially blocked the inactivation of the enzyme by the compound, indicating that the compound inactivated sulfatase at the active site. The irreversible nature of the enzyme-inhibitor interaction was supported by irreversibility studies. Thus, (p-O-sulfamoyl)-N-alkanoyl tyramines represent a new series of non-steroidal estrone sulfatase inhibitor.
...
PMID:Synthesis and sulfatase inhibitory activities of non-steroidal estrone sulfatase inhibitors. 900 36

Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than in plasma, presumably due to in situ formation of estrogen. Several lines of evidence indicate that the major source of estrogen in breast cancer cells may be from conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estrone sulfatase may thus be potential agents for the treatment of estrogen-dependent breast cancer. We designed and synthesized a series of estrone-3-amino derivatives as potential estrone sulfatase inhibitors. We tested the inhibitory potential of these compounds using human placental microsomes, which contain a substantial amount of estrone sulfatase activity. Several compounds in the series significantly inhibited estrone sulfatase activity of the human placental microsomes when present at 10 microM. The IC50 for the estrone-3-amino compounds ranged from 8.7 to 14.6 microM. We next tested the ability of the estrone-3-amino derivatives to inhibit growth of the estrogen-dependent MCF-7 breast cancer cell line. MCF-7 cells showed substantial proliferation in the presence of 100 nM estrone sulfate in estrogen-free media, indicating that the cells were capable of converting estrone sulfate into estrone. The proliferative effect of estrone sulfate (1 microM) was significantly blocked by the estrone-3-amino derivatives at 10 microM. The magnitude of MCF-7 cell inhibition resulting from treatment with the estrone-3 amino compounds was similar to or exceeded that of Danazol, but was less than the level resulting from treatment with estrone sulfamate. Using data from all of the compounds tested, inhibition of MCF-7 cell proliferation was positively correlated with inhibition of placental estrone sulfatase activity, suggesting that the reduction in cell growth was attributable to the blockade of sulfatase activity. In support of this, there was no relationship between inhibition of estrone sulfatase activity and inhibition of cell growth when the estrogen-independent cell line MDA-MB-231 was used. Our results indicate the possible utility of estrone-3-amino derivatives for inhibition of estrone sulfatase activity. Further, our data support the concept that estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers.
...
PMID:Inhibition of placental estrone sulfatase activity and MCF-7 breast cancer cell proliferation by estrone-3-amino derivatives. 900 41

In order to investigate the influence of estrogen metabolism on human breast cancer, estradiol 2- and 16 alpha-hydroxylase (2- and 16 alpha-OHase) activities were determined in the microsomal fractions of cancer tissues by using reverse phase HPLC. 2-OHase activity was detected in most cancer tissues and noncancerous tissues, but the activity was significantly lower in cancer tissues than in the paired noncancerous tissues (0.01 < p < 0.02). Interestingly the patients without lymph node metastasis had significantly higher 2-OHase activity in cancer tissues than those with lymph node metastasis (0.02 < p < 0.05). No correlation was observed between ER status and 2-OHase activity in cancer tissues. On the other hand, 16 alpha-OHase activity was detected only in one third of the breast cancer tissues examined. The activity was not significantly different from that in noncancerous tissues, although it was relatively higher in ER-positive cancer tissues when compared with that in ER-negative ones (0.05 < p < 0.1). Estrone sulfatase activity measured simultaneously in the cytosol fractions of some specimens was much higher in cancer tissues than in noncancerous tissues (0.02 < p < 0.05). We found, however, no correlation between estrone sulfatase activity and estradiol hydroxylase activity. Taken together, our results suggest that the increase in 2-OHase activity prevents the proliferation of breast cancer and that estradiol metabolism is regulated independently of the local biosynthesis of estrogen.
...
PMID:Influence of estrogen metabolism on proliferation of human breast cancer. 911 18

Recently, we reported the synthesis and biomedical studies of a series of (p-O-sulfamoyl)-N-alkanoyl tyramines as nonsteroidal estrone sulfatase inhibitors. One of the most potent inhibitors in this series is (p-O-sulfamoyl)-N-tridecanoyl tyramine 1 with an 1C50 value of 61.3 nM. In this study, we synthesized four analogs of 1 (compounds 2-5) to investigate the structure-activity relationships of the amide functionality in (p-O-sulfamoyl)-N-tridecanoyl tyramine. Replacement of the amide functionality in 1 with an ethylene moiety to form the alkyl analog 5 resulted in complete loss of sulfatase inhibitory activity (IC50 of 61.3 nM vs. > 20 microM). The keto, hydroxy, and ester analogs (inhibitors 2-4) are 8-15 times less in affinity to the sulfatase than inhibitor 1. However, their inhibitory activities are significantly higher than the alkyl analog 5. The results suggest that the amide functionality is favorable for sulfatase inhibitory activity and that there may be a hydrogen bonding component to the enzyme interaction in this region.
...
PMID:Structure-activity relationship studies of the amide functionality in (p-O-sulfamoyl)-N-alkanoyl tyramines as estrone sulfatase inhibitors. 925 92


<< Previous 1 2 3 4 5 6 Next >>

---