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

Raobaikady, Bindumalini; Reed, Michael J.; Leese, Mathew P.; Potter, Barry V. L.; Purohit, Atul

doi:10.1002/ijc.21066

Cited by 25 publications

(34 citation statements)

References 37 publications

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“…It is now known that sulphamoylated derivatives of oestrogens have a superior pharmacokinetic profile and are more resistant to metabolism than their non-sulphamoylated counterparts (Newman et al, 2006). 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).…”

Section: Discussionmentioning

confidence: 99%

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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%

“…2-MeOE2bisMATE is thought to act like 2-MeOE2, by binding to the colchicine-binding site on tubulin and altering microtubule stability (MacCarthy-Morrogh et al, 2000;Raobaikady et al, 2005). It induces Bcl-2 phosphorylation and apoptosis in endothelial and cancer epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Studies conducted with a range of cell lines have shown that STX243 is equipotent to STX140 at inhibiting cell proliferation (Suzuki et al, 2003;Raobaikady et al, 2005). Novel experiments recently conducted by our group have shown that STX243, and also STX140, induce G 2 /M arrest and apoptosis in cells recovered from xenograft tumours .…”

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confidence: 99%

“…Earlier studies have also shown that STX140 initiates apoptosis, possibly by phosphorylating BCL-2 and activating caspases 3 and 9 (Day et al, 2003;Wood et al, 2004). In vitro STX140 has been shown to inhibit cell proliferation, including preventing the growth of cells that are resistant to conventional chemotherapeutic agents (Suzuki et al, 2003;Raobaikady et al, 2005). In vivo investigations have shown that STX140 is orally effective at inhibiting the growth of both oestrogen-receptor-positive (ER þ ) and oestrogen-receptornegative (ERÀ) tumours (Ireson et al, 2004;Utsumi et al, 2005).…”

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confidence: 99%

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer

et al. 2008

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The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg À1 oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg À1 dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.

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“…The problems of poor bioavailability and rapid metabolism associated with this drug may be overcome by synthesising analogues resistant to conjugative and metabolic inactivation (Leese et al, 2005b). One such compound is 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), whose potential anti-angiogenic and anti-tumour activities have been well documented (Day et al, 2003;Ho et al, 2003;Newman et al, 2004;Wood et al, 2004;Raobaikady et al, 2005;Utsumi et al, 2005;Leese et al, 2006).…”

mentioning

confidence: 99%

The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers

Newman

Foster

et al. 2007

Br J Cancer

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Therapies for hormone-independent prostate and breast cancer are limited, with the effectiveness of the taxanes compromised by toxicity, lack of oral bioavailability and drug resistance. This study aims to identify and characterise new microtubule disruptors, which may have improved efficacy relative to the taxanes in hormone-independent cancer. 2-Methoxy-3-O-sulphamoyl-17b-cyanomethyloestra-1,3,5(10)-triene (STX641), 2-methoxy-3-hydroxy-17b-cyanomethyl-oestra-1,3,5(10)-triene (STX640) and 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140) were all potent inhibitors of cell proliferation in a panel of prostate and breast cancer cell lines. STX641 and STX640 significantly inhibited tumour growth in the MDA-MB-231 xenograft model. STX641 inhibited both in vitro and in vivo angiogenesis. Despite good in vivo activity, STX641 was not as potent in vivo as STX140. Therefore, STX140 was evaluated in the prostate hormone-independent PC-3 xenograft model. STX140 had superior efficacy to docetaxel, 2-MeOE2 and bevacizumab. In contrast to vinorelbine, no significant toxicity was observed. Furthermore, STX140 could be dosed daily over a 60-day period leading to tumour regression and complete responses, which were maintained after the cessation of dosing. This study demonstrates that STX641 and STX140 have considerable potential for the treatment of hormone-independent breast and prostate cancer. In contrast to the taxanes, STX140 can be dosed orally, with no toxicity being observed even after prolonged daily dosing.

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

Cited by 25 publications

References 37 publications

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

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

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer

The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers

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