IN-VITRO AND IN-VIVO ANTITUMOR-ACTIVITY OF THE PHOSPHATIDYLINOSITOL-3-KINASE INHIBITOR, WORTMANNIN

The microbial product wortmannin has previously been shown to be a pot ent inhibitor of phosphatidylinositol-3-kinase. In view of the potenti al role of this enzyme in transduction of mitogenic signals, we determ ined the cytotoxic activity of wortmannin against several human tumor cell lines in vitro. The most sensitive lines included GC3 colon carci noma, IGROV1 ovarian carcinoma, and CCRF-CEM leukemia (IC-50s ranging from 0.7-2. 1 mu M) The cytotoxicity of wortmannin was decreased appro ximately 10-fold by serum-free conditions Wortmannin was generally les s active in low passage human breast cancer cell lines that overexpres s either epidermal growth factor receptor ol Her2/neu. Wortmannin was also tested for in vivo antitumor activity against seven murine tumor and ten human tumor xenograft models. Activity (>60% inhibition of tum or. growth) was observed in only the C3H mammary carcinoma and the hum an BxPC-3 pancreatic carcinoma xenograft. In vivo antitumor activity d id not correlate with in vitro sensitivity to wortmannin cytotoxicity.