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2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer

Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.
British Journal of Cancer (Impact Factor: 4.82). 12/2008; 99(11):1842-8. DOI: 10.1038/sj.bjc.6604752
Source: PubMed

ABSTRACT Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

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    • "One such compound is STX140 (2-methoxyestradiol-bis-sulfamate; Figure 1) which shows oral efficacy against a range of in vitro cancer cell lines and in vivo xenograft tumor models [3]–[16]. Our previous work demonstrates that in breast cancer cells STX140, as measured by tubulin binding assays [4] and as observed in MCF-7 cells using immunohistochemistry [17], causes microtubule disruption and therefore tubulin destabilisation. "
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    ABSTRACT: Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer.
    PLoS ONE 12/2013; 8(12):e80305. DOI:10.1371/journal.pone.0080305 · 3.23 Impact Factor
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    • "Antiproliferative activity induced by 2-methoxyestradiol-bis-sulphamate was detected in the estrogen receptor positive human breast adenocarcinoma MCF-7 cell line (0.1–1 μM), prostate cancer cell line (LNACaP), tumorigenic estrogen receptor negative breast adenocarcinoma cell line (MDA-MB-231), esophageal carcinoma SNO cells, HeLa and the CAL51 human breast carcinoma cell line [26], [27], [28], [29], [30], [31], [32], [33]. In vivo antiproliferative activity was discovered in xenografts derivative of estrogen receptor positive human breast adenocarcinoma wild type cell line (MCF-7WT), mitoxantrone resistant breast adenocarcinoma cell line (MCF-7 MR), drug resistant human adenocarcinoma cell line (MCF-7 DOX40), prostate cancer cell line (LNACaP), MDA-MB-435 and prostate hormone independent PC-3 xenograft model [31], [34], [35], [36], [37], [38], [39]. "
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    PLoS ONE 09/2013; 8(9):e71935. DOI:10.1371/journal.pone.0071935 · 3.23 Impact Factor
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    • "However, it is becoming extensively clear that many oncogene-activated signalling pathways converge towards an adaptation of tumor cell metabolism to provide energy and essential biomolecules required for the rapid cell division [4] [5] [6]. Within the last years, a large variety of different solid tumors have been associated with increased metabolism (i.e., prostate cancer [7], breast cancer [8], glioblastoma [9], ovarian carcinoma [10], pancreatic cancer [11], and many others). It is now accepted that the metabolism of cancer cells has extremely unique characteristics compared to the one of healthy nonproliferating cells [4]. "
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