Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198
Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is me...
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Published in | Molecular cancer therapeutics Vol. 7; no. 6; pp. 1472 - 1482 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.06.2008
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Subjects | |
Online Access | Get full text |
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Summary: | Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment
is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent
safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position
17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues
with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198,
ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with
hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels
compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G 2 -M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1α levels. ENMD-1198 and ENMD-1200 showed improved
in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in
an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung
carcinoma metastatic model ( P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide.
ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients
with refractory solid tumors. [Mol Cancer Ther 2008;7(6):1472–82] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-08-0107 |