Significant antitumor activity <i>in vivo</i> following treatment with the microtubule agent ENMD-1198

LaVallee, Theresa; Burke, Patricia A.; Swartz, Glenn M.; Hamel, Ernest; Agoston, Gregory E.; Shah, Jignesh; Suwandi, Lita S.; Hanson, Art D.; Fogler, William E.; Sidor, Carolyn; Treston, Anthony M.

doi:10.1158/1535-7163.mct-08-0107

Cited by 66 publications

(65 citation statements)

References 30 publications

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“…ENMD-1198 was 2.5-to 6-fold more potent than 2ME2 at inhibiting human endothelial cell proliferation depending on the concentrations compared and the cell type. These results are consistent with those obtained with the fibroblast cell line MRC-5 (Supplementary Table S1) and those previously reported for another endothelial cell type (human umbilical vascular endothelial cell) and a variety of human cancer cell lines (19). Furthermore, our results show that, in addition to its improved antiproliferative activity, ENMD-1198 also more potently inhibits endothelial cell motility, chemotaxis, and morphogenesis into capillary-like structures.…”

Section: Discussionsupporting

confidence: 92%

“…The most promising of these analogues, ENMD-1198, has been selected as a lead compound and is currently being tested in phase I clinical trials in patients with refractory solid tumors. In preclinical studies, ENMD-1198 retained potent antitumor properties while displaying improved metabolic stability (19). In the present study, we have shown that ENMD-1198 is a potent antivascular agent.…”

Section: Discussionsupporting

confidence: 54%

“…However, its bioavailability seems to be a limiting factor (12,13,17). To improve the metabolic stability and antitumor efficacy of 2ME2, a series of analogues has been generated (18,19). The most promising of these analogues, ENMD-1198, has been selected as a lead compound and is currently being tested in phase I clinical trials in patients with refractory solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…From this series, three molecules were found to have improved metabolic stability and antiproliferative properties (19). One compound, ENMD-1198, was selected as the lead molecule of this series and is currently being tested in a phase I clinical trial in patients with refractory solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Pasquier

Sinnappan

Munoz

et al. 2010

Molecular Cancer Therapeutics

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The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrowderived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Pasquier

Sinnappan

Munoz

et al. 2010

Molecular Cancer Therapeutics

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“…2-Methoxyestradiol-3,17-O,O-bis-sulphamate (2MEbi-sMATE) was designed with the above concepts in mind and is currently undergoing clinical trials as STX140 [20]. 2MEbisMATE has a positive prolife for anti-cancer and anti-angiogenic activities.…”

Section: Discussionmentioning

confidence: 99%

Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

Theron

Prudent²,

Nolte

et al. 2014

Cancer Chemother Pharmacol

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overexpressing multidrug-resistant uterine sarcoma cell line. The non-sulphamoylated compounds were only cytotoxic at micromolar ranges, if at all. The sulphamoylated compounds inhibited pure tubulin polymerization in a dose-dependent manner and induced microtubule destruction in cells after 24-h exposure. Conclusion Results revealed that the novel sulphamoylated 2ME derivatives have potential as anti-cancer drugs, possibly even against chemoresistant cancer cells. These compounds disrupt the intracellular microtubule integrity which leads to mitotic block of the cells.

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In vitro changes in mitochondrial potential, aggresome formation and caspase activity by a novel 17‐β‐estradiol analogue in breast adenocarcinoma cells

Nkandeu

Mqoco

Visagie

et al. 2013

Cell Biochemistry & Function

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2-Methoxyestradiol, a natural metabolite of estradiol, exerts antiproliferative and antitumour properties in vitro and in vivo. Because of its low oral bioavailability, several promising analogues of 2-methoxyestradiol have been developed. In this study, the in vitro influence of the compound, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (C19), a non-commercially available 17-β-estradiol analogue, was tested on the breast adenocarcinoma MCF-7 cell line. The in vitro influence of 24 h exposure to 0.18 μM of C19 on MCF-7 cells was evaluated on cell morphology, cell cycle progression and possible induction of apoptosis and autophagy. Polarization-optical transmitted light differential interference contrast and fluorescence microscopy revealed the presence of cells blocked in metaphase, occurrence of apoptotic bodies and compromised cell density in C19-treated cells. Hallmarks of autophagy, namely an increase in the number of acidic vacuoles and lysosomes, were also observed in C19-treated samples. An increase in the number of cells present in the sub-G1 fraction, as well as a reduction in mitochondrial membrane potential was observed. No significant alterations in caspase 8 activity were observed. A twofold increase in aggresome formation was observed in C19-treated cells. C19 induced both apoptosis and autophagy in MCF-7 cells.

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Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198

Cited by 66 publications

References 30 publications

ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

In vitro changes in mitochondrial potential, aggresome formation and caspase activity by a novel 17‐β‐estradiol analogue in breast adenocarcinoma cells

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