Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application

Elger, W.; Schwarz, S.; Hedden, Annemarie; Reddersen, Gudrun; Schneider, Birgitt

doi:10.1016/0960-0760(95)00214-6

Cited by 150 publications

(118 citation statements)

References 13 publications

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“…Oestrogen sulphamates, such as oestrone-3-Osulphamate (EMATE) were originally identified as potent STS inhibitors, a property shared with 2-MeOE2bisMATE (Raobaikady et al, 2005). EMATE was not developed for breast cancer therapy as it became evident that oestrogen sulphamates had enhanced oestrogenicity when administered orally to rats (Elger et al, 1995). In a uterine weight gain assay, oestradiol sulphamate proved to be five times more active than ethinyloestradiol and 100 times more active than oestradiol, on oral application.…”

Section: Discussionmentioning

confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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“…Unexpectedly, EMATE proved to be a potent oestrogen on oral application in rats (Elger et al, 1995). The observed oestrogenicity of oestrogen sulphamates, such as EMATE, is thought to be a consequence of their sequestration into red blood cells (RBCs) and slow release of the oestrogen moiety into plasma (Elger et al, 1998).…”

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confidence: 99%

Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents

et al. 2004

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2-Methoxyoestradiol (2-MeOE2) is an endogenous oestrogen metabolite that inhibits the proliferation of cancer cells in vitro, and it is also antiangiogenic. In vivo 2-MeOE2, when administered at relatively high doses, inhibits the growth of tumours derived from breast cancer cells, sarcomas and melanomas. Sulphamoylated derivatives of 2-MeOE2 are more potent inhibitors of in vitro breast cancer cell growth than 2-MeOE2. In the present study, we have compared the pharmacokinetic profiles and metabolism of 2-MeOE2 and its sulphamoylated derivative, 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE), in adult female rats. Their ability to inhibit tumour growth was compared in nude mice bearing xenografts derived from MDA-MB-435 (oestrogen receptor negative) melanoma cancer cells. After a single oral 10 mg kg À1 dose of 2-MeOE2bisMATE, significant concentrations of this compound were still detectable at 24 h. In contrast, no 2-MeOE2 or metabolites were detected in plasma at any time after a 10 mg kg À1 oral dose. Thus, the bioavailability of 2-MeOE2 is very low, whereas for 2-MeOE2bisMATE it was 85%. No significant metabolites of 2-MeOE2bisMATE were detected in plasma after oral or intravenous dosing, showing that this drug is resistant to metabolism. In the tumour efficacy model, oral administration of 2-MeOE2bisMATE, at 20 mg kg À1 day À1 daily for 28 days, almost completely inhibited tumour growth. Inhibition of tumour growth was maintained for a further 28 days after the cessation of dosing. At this dose level, 2-MeOE2 did not inhibit tumour growth. The resistance to metabolism shown by 2-MeOE2bisMATE and its ability to inhibit tumour growth in vivo suggest that this compound should have considerable potential for development as a novel anticancer drug.

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“…11,12 Unexpectedly, EMATE proved to be a potent estrogen on oral application in the rat. 13 This is thought to result from its absorption into red blood cells after ingestion thus protecting it from inactivation during transit through the liver. 14 To produce a non-estrogenic sulfatase inhibitor a number of A-ring modified compounds were synthesized and tested.…”

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Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

Newman

Leese

Purohit

et al. 2004

Intl Journal of Cancer

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Sulfamoylation of 2-methoxyestrone (2-MeOE1) was shown previously to enhance its potency as an anti-proliferative agent against breast cancer cells. We have examined the ability of a series of 2-methoxyestradiol (2-MeOE2) and 2-ethylestradiol (2-EtE2) sulfamates to inhibit angiogenesis in vitro. 2-MeOE2 bis-sulfamate and 2-EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 values of 0.05 M and 0.01 M, respectively. A novel co-culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti-angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Key words: angiogenesis; breast cancer; estrogens; estrogen sulfamates; microtubulesEstrogens can be metabolised via either a 2-hydroxylase or 16␣-hydroxylase pathway and there is a growing awareness that the route of estrogen metabolism may influence the development of breast tumors. 2-Hydroxyestrogens and their 2-methoxy derivatives are non-estrogenic whereas 16␣-hydroxy metabolites are estrogenic due, in part, to their ability to form adducts with proteins. 1,2 Research carried out by Bradlow and others 3,4 has indicated that although the 2-hydroxylase pathway is associated with a reduced risk of breast cancer, increased formation of 16␣-hydroxy metabolites may increase breast cancer risk. It was suggested recently that the major derivative of 2-hydroxyestrogens, 2-methoxyestradiol (2-MeOE2, Fig. 1) may in fact be the endogenous estrogen metabolite that inhibits breast carcinogenesis. 5 2-MeOE2 is currently undergoing Phase I/II trials as a novel agent for breast cancer therapy. 6 Its selection for development as an anti-cancer agent was based on its ability to inhibit the proliferation of a wide range of cancer cells including estrogen receptor positive (ERϩ) and negative (ERϪ) breast cancer cells. 7,8 In vivo oral administration of 2-MeOE2 inhibited the growth of Meth-A sarcoma, B16 melanoma and human MDA-MB-435 breast carcinomas. 8,9 Relatively high doses of 2-MeOE2 (75-100 mg/kg/day) were administered to produce the reductions in tumor growth. In addition to its anti-proliferation effects 2-MeOE2 was also identified as the active ingredient of urine extracts that was able to inhibit angiogenesis. 9 Using brain-derived capillary endothelial cells 2-MeOE2 was found to be a specific inhibitor of the proliferation of these cells being 90ϫ more potent than 2-methoxyestrone (2-MeOE1) and 250ϫ more potent than estradiol. Several subsequent investigations have confirmed the potency of 2-MeOE2 as an inhibitor of endothelial cell growth and angiogenesis in vitro and in vivo. 8,10 The mechanism(s) by which 2-MeOE2 inhibits endothelial cell growth and angiogenesis remains to be elucidated.The estrogen sulfamate, estrone-3-O-sulfamate (EMATE) was initially identified as a potent steroid sulfatase inhibitor. 11,12 Unexpectedly, EMATE proved to be a potent estroge...

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Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application

Cited by 150 publications

References 13 publications

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

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