In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002)

Phosphatidylinositol 3-kinase (PI3-K) induces mitogenesis, cell growth, and cell transformation. Amplification of the gene encoding the P110 alpha sub unit likely is an important event in ovarian cancer progression, and PI3-K inhibitors are possible therapeutic agents for this disease. We evaluated e ffects of LY294002, a potent inhibitor of PI3-K, on growth of ovarian carci noma in vivo and in vitro, and on ascites formation in vivo. Athymic mice w ere inoculated i.p. with the ovarian cancer cell line OVCAR-3, Seven days a fter inoculation, mice were treated with or without LY294002 (100 mg/kg of body weight) for 3 weeks. Body weight and abdominal circumference were meas ured twice weekly. At the end of the experiment, mice were sacrificed, asci tes volume was measured, and tumors were excised. Mean tumor burden in the LY294002-treated group was reduced by similar to 65% versus controls. Virtu ally no ascites developed in the treatment group; mean volume of ascites in controls was 3.3 +/- 0.38 mi, OVCAR-3 cells also were cultured in vitro wi thout and with LY294002 (1, 5, and 10 mu M) for 24 h, The number of cells i n 1, 5, and 10 mu M LY294002-treated wells was reduced by 27, 56, and 75%, respectively, versus controls. In vivo and in vitro morphological studies d emonstrated that LY294002 induced marked nuclear pyknosis and diminished cy toplasmic volume in the tumor cells, confirmed as apoptosis, Thus, LY294002 significantly inhibits growth and ascites formation of ovarian carcinoma i n vivo and markedly inhibits ovarian cancer cell proliferation in vitro, su ggesting an important role of PI3-K inhibitors as a potentially useful trea tment for women with ovarian carcinoma.