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A Second Generation 2-Methoxyestradiol Prodrug Is Effective Against Barrett's Adenocarcinoma in a Mouse Xenograft Model
Kambhampati, Suman Rajewski, Roger A. Tanol, Mehmet Haque, Inamul Das, Amlan Bangerjee, Snigdha Jha, Saheli Burns, Douglas Reyes, Emma Borrego-Diaz Van Veldhuizen, Peter J.
Kambhampati, Suman
Rajewski, Roger A.
Tanol, Mehmet
Haque, Inamul
Das, Amlan
Bangerjee, Snigdha
Jha, Saheli
Burns, Douglas
Reyes, Emma Borrego-Diaz
Van Veldhuizen, Peter J.
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Abstract
2-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem we have now synthesized and tested a new prodrug of 2-ME2 that is water soluble due to a bio-reversible hydrophilic group added at the 3-position and more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anti-cancer agent for both in vitro and in vivo studies against Barrett's esophageal adenocarcinoma (BEAC), and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule-network.
Description
This is the author's accepted manuscript. The original is available at http://mct.aacrjournals.org/content/12/3/255
Date
2016-01-27
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Publisher
American Association for Cancer Research
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Keywords
2-Methoxyestradiol, Esophageal cancer, Chemotherapy, Prodrug
Citation
Kambhampati, S., R. A. Rajewski, M. Tanol, I. Haque, A. Das, S. Banerjee, S. Jha, D. Burns, E. Borrego-Diaz, P. J. Van Veldhuizen, and S. K. Banerjee. "A Second-Generation 2-Methoxyestradiol Prodrug Is Effective against Barrett's Adenocarcinoma in a Mouse Xenograft Model." Molecular Cancer Therapeutics 12.3 (2013): 255-63. http://dx.doi.org/10.1158/1535-7163.MCT-12-0777