2-methoxyestrone and Carcinoma--Lewis-Lung

A prodrug strategy was investigated to address the problem of limited aqueous solubility and the resulting limited bioavailability of the antitumor agent 2-methoxyestradiol. The 3-phosphate, 17-phosphate, and 3,17-diphosphate of 2-methoxyestradiol were synthesized. 2-methoxyestradiol 3-phosphate was metabolized more efficiently to the parent compound in vivo than 2-methoxyestradiol 17-phosphate, and it was also more cytotoxic in cancer cell cultures than either the 17-phosphate or the 3,17-diphosphate. These results agree with the in vivo anticancer activity of 2-methoxyestradiol 3-phosphate in a mouse Lewis lung carcinoma experimental metastasis model as opposed to the 17-phosphate and 3,17-diphosphate, both of which were inactive. The in vivo antitumor activity of 2-methoxyestradiol 3-phosphate at a dose of 200 mg/kg per day was comparable to that of a maximally tolerated dose of cyclophosphamide.

Topics: 2-Methoxyestradiol; Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Line, Tumor; Drug Screening Assays, Antitumor; Estradiol; Humans; Male; Mice; Mice, Inbred C57BL; Organophosphates; Prodrugs; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship