14-o-phosphonooxymethyltriptolide and Ovarian-Neoplasms

A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780).

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Colon; Colonic Neoplasms; Diterpenes; Drug Stability; Epoxy Compounds; Female; HT29 Cells; Humans; Mice; Mice, Nude; Organophosphates; Ovarian Neoplasms; Ovary; Phenanthrenes; Prodrugs; Solubility

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo.. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth.. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice.. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diterpenes; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Electric Impedance; Epoxy Compounds; Female; Humans; Mice; Mice, Nude; Neoplasms, Glandular and Epithelial; Organophosphates; Ovarian Neoplasms; Paclitaxel; Phenanthrenes; Prodrugs; Xenograft Model Antitumor Assays