title: Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate.
abstract: Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER alpha and ER beta and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kanako
authors.initials: K
authors.lastname: Okamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Sekimoto
authors.forename: Y R Santosh
authors.initials: YR
authors.lastname: Laxmi
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000494:pharmacology*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy*; D002273:Carcinogens; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010755:Organophosphates / Q000494:pharmacology*; D010766:Phosphorylation; D011355:Prodrugs; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D020847:Estrogen Receptor Modulators; D010755:Organophosphates; D011355:Prodrugs; D020845:Selective Estrogen Receptor Modulators; C527360:raloxifene diphosphate; D020849:Raloxifene Hydrochloride; D015127:9,10-Dimethyl-1,2-benzanthracene