title: A second-generation 2-Methoxyestradiol prodrug is effective against Barrett's adenocarcinoma in a mouse xenograft model.
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 bioreversible hydrophilic group added at the 3-position and that 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 anticancer agent for both in vitro and in vivo studies against Barrett 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.
authors.affiliation: Cancer Research Unit, VA Medical Center, Kansas City, MO, USA. skambhampati@kumc.edu
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
authors.forename: Mehmet
authors.initials: M
authors.lastname: Tanol
authors.forename: Inamul
authors.initials: I
authors.lastname: Haque
authors.forename: Amlan
authors.initials: A
authors.lastname: Das
authors.forename: Snigdha
authors.initials: S
authors.lastname: Banerjee
authors.forename: Saheli
authors.initials: S
authors.lastname: Jha
authors.forename: Douglas
authors.initials: D
authors.lastname: Burns
authors.forename: Emma
authors.initials: E
authors.lastname: Borrego-Diaz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Veldhuizen
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
mesh_terms: D000077584:2-Methoxyestradiol; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D011355:Prodrugs; D004958:Estradiol; D000077584:2-Methoxyestradiol