The development of steroid sulphatase inhibitors

Reed, M. J.; Purohit, Atul; Woo, L. W. Lawrence; Potter, Barry V. L.

doi:10.1677/erc.0.0030009

Cited by 68 publications

(56 citation statements)

References 6 publications

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“…42 It is interesting to note that oestrogen sulphamates are also potent irreversible inhibitors of steroid sulphatase (STS), an enzyme responsible for the production of biologically active oestrogens in hormone-dependent breast, ovarian, and endometrial cancer cells. [43][44][45] The importance of STS in the progression of hormone-dependent tumours has been well documented. 43,44 It has been reported previously that C-2-substituted sulphamoylated oestrogens, such as 2-MeOEMATE and 2-MeOE2bisMATE, also inhibited STS enzyme both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…[43][44][45] The importance of STS in the progression of hormone-dependent tumours has been well documented. 43,44 It has been reported previously that C-2-substituted sulphamoylated oestrogens, such as 2-MeOEMATE and 2-MeOE2bisMATE, also inhibited STS enzyme both in vitro and in vivo. 46,47 2-Ethyl-substituted compounds such as 2-EtE2-MATE and 2-EtE2bisMATE also inhibit STS activity with IC 50 values of 0.92 and 0.9 lM, respectively, in placental microsomes.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

et al. 2005

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A natural metabolite of oestradiol (E2), 2-methoxyoestradiol (2-MeOE2), exerts both antitumour and antiangiogenic effects. 2-MeOE2 is currently in clinical trials for the treatment of a variety of cancers. We have previously shown that a number of sulphamoylated analogues of 2-MeOE2 possess enhanced potency and bioavailability with respect to 2-MeOE2. In our study, the effects of C-2-substituted E2 derivatives, with sulphamoylation at the C-3 and/or C-17 position, on ERa 2ve MDA-MB-231 breast cancer cells were evaluated. Sulphamoylated derivatives were potent inhibitors of cell proliferation, and these effects were irreversible when compared to growth inhibitory effects induced by 2-MeOE2. Cell cycle analysis suggested that these derivatives caused cells to arrest at the G2-M phase of the cell cycle. Sulphamoylated analogues suppressed the clonogenic potential of MDA-MB-231 cells and also their growth on Matrigel 1 culture substratum. Immunofluorescence studies showed fragmented nuclear bodies and an abnormal microtubule cytoskeleton in cells exposed to one of the potent compounds, 2-MeOE2-bis-sulphamate. In addition, these analogues induced phosphorylation of BCL-2, a protein considered to be the guardian of microtubule integrity. In each of the assays, the sulphamoylated derivatives were at least 10-fold more potent than the parent compound 2-MeOE2. In view of the enhanced potencies associated with sulphamoylated E2 derivatives in ERa 2ve cells, these analogues should hold considerable therapeutic potential for the treatment of hormone-independent breast cancers. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

et al. 2005

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“…Furthermore, the halflife of E1S in plasma (10 -12 hours) is considerably longer than that for estrone and estradiol (20 -30 minutes). E1S is therefore thought to act as a reservoir for the formation of active estrogens via the action of STS [8]. This enzyme converts E1S to estrone that is then reduced to the biologically active estrogen, estradiol, by 17␤-HSD1, which is overexpressed in many breast tumors (Fig.…”

Section: Stsmentioning

confidence: 99%

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

et al. 2007

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Key Words. Breast cancer • Estrogen • Estrone sulfate • Steroid sulfatase • Sulfatase inhibitor LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss the role of steroid sulfatase in regulating estrogen production in postmenopausal women.2. Describe the potential of steroid sulfatase inhibition in cancer therapy.3. Discuss a potential new endocrine therapy for patients progressing on aromatase.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTInhibitors 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.

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“…Plasma and tissue concentrations of E1S in humans are considerably higher than those of unconjugated oestrone and oestradiol (Noel et al, 1981;Pasqualini et al, 1996). It has been suggested that the high plasma and tissue levels of E1S may act as a reservoir for the formation of biologically active steroids by the action of steroid sulphatase (STS) (Reed et al, 1996). The activity of STS, the enzyme that hydrolyses E1S to oestrone, is considerably higher than that of the aromatase enzyme in breast tumours (James et al, 1987).…”

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confidence: 99%

“…Since many tumours will fail to respond to endocrine therapy, or progress after a relatively short period of time, it is necessary to continue to develop new drugs for the treatment of breast cancer. A number of potent STS inhibitors have now been developed (Howarth et al, 1994;Reed et al, 1996), of which 667 COUMATE (Figure 1) Woo et al, 2000) has recently entered a Phase I clinical trial in postmenopausal women with breast cancer.…”

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Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats

et al. 2004

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Breast cancer is a major cause of mortality in Western countries and there is an urgent requirement for novel treatment strategies. The nonsteroidal sulphatase inhibitor 667 COUMATE inhibits hepatic steroid sulphatase and growth of oestrone sulphate stimulated tumours in the nitrosomethylurea-induced rat mammary model. Other compounds that contain an aryl sulphamate moiety, for example, oestrone-3-O-sulphamate, are sequestered into red blood cells (RBCs). The aims of this study were to determine the pharmacokinetics of 667 COUMATE and to investigate its sequestration into RBCs. We administered a single p.o. or i.v. dose (10 mg kg À1 ) of 667 COUMATE to rats and used a high-performance liquid chromatography method to measure the levels of the agent and its putative metabolites in plasma. 667 COUMATE had a bioavailability of 95% and could be detected in plasma for up to 8 h. Using two independent analytical methods, we demonstrated that 667 COUMATE is sequestered by RBCs both ex vivo and in vivo. Previous investigations have revealed that 667 COUMATE is rapidly degraded in plasma ex vivo. In this study, we demonstrate that 667 COUMATE is stabilised due to its sequestration into RBCs. In conclusion, the pharmacological efficacy and high oral bioavailability of 667 COUMATE may be partly a consequence of the ability of RBCs to both protect the agent from metabolic degradation and facilitate its transport to tissues. These data support the further clinical evaluation of this novel endocrine therapeutic agent.

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The development of steroid sulphatase inhibitors

Cited by 68 publications

References 6 publications

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiolmono- andbis-3-O-sulphamates

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats

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