Department for General Surgery and Thoracic Surgery, Christian Albrecht
University, Arnold-Heller-Strasse 7, 24105 Kiel, Germany, boehle@surgery.uni-kiel.de
BACKGROUND AND AIMS. Recently we demonstrated that phosphatidylinositol 3-kinase
(PI3K) is overexpressed in human lung cancer. This study evaluated whether the
PI3K inhibiting agent wortmannin affects proliferation of human lung cancer
cells in vitro and in vivo. METHODS. Effects of exposure of human non-small-cell
lung cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in
vitro by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we
examined the effects of blocking PI3K by wortmannin prior to xenotransplantation
of human NSCLC cells into SCID-bg mice and the effect of systemic wortmannin
administration following intrapulmonary xenotransplantation of human NSCLC.
RESULTS. Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin
inhibited proliferation in correlation to concentration in vitro. In vivo the
blocking of PI3K by wortmannin prior to xenotransplantation caused a significant
delay in the growth of subcutaneously induced tumors. Systemic wortmannin
administration increased mean survival after intrapulmonary xenotransplantation
of human NSCLC significantly by 38% and 47%. CONCLUSIONS. These data suggest
inhibition of PI3K activity as a potential target for treatment of human NSCLC.
Systemic toxicity of wortmannin requires development of improved PI3K inhibitors
with favorable pharmacological properties.
