摘要

The present study was designed to select the effective dosage range of Z24 [3Z-3-[(1H-pyrrol-2-yl)-inethylidenel-1-(I-piperidinylmethyl)- 1,3-2H-indol-2-one], a novel synthetic indolin-2-ketone small-molecule compound, against tumorigenesis and angiogene is in vitro and in vivo and to investigate the primary action mechanism of Z24 on the angiogenesis by comparing with SU5416 [3-[2,4-dimethylpyrrol-5 -yl)methyllidenyl] -indolin-2 -one] in the selective effects on vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF) signaling and Bcl-2-related cell vitality because Z24 is a potential inhibitor of the Bel-2 that inhibits growth of multiple tumor types in vivo in our previous study. Per os Z24 inhibited dose-dependently the mouse S180 xenograft tumor growth and angiogenesis in mouse subcutaneous (s.c.) Matrigel plugs in vivo. The maximum growth inhibitory rate was 56.1% by 80 mg/kg/day on SI 80 mouse sarc)ma cells; however. the maximum inhibitory potency on angiogenesis in C57BL/6 mouse Subcutaneous Matilgel plug model was 50 mg/k,/day. Z24 inhibited angiogenesis in chicken chorioallantoic membrane (CAM) and invasion and inhibited tube formation of endothelial cells in a dosedependent manner. Compared with SU5416, the IC50 (50% inhibition concentration) of Z24 on the proliferation of ECV-304 carcinoma cells induced by VEGF or bFGF was 24.4 and 17.99 muM, respectively, which is higher or lower, respectively, than that of SU5416 (14.2 muM for VEGF and 22.7 muM for bFGF). Furthermore, the IC50 of Z24 on the proliferation of Bcl-2 over-expressing HeLa cells and ron-Bcl-2expressing (wild-type) HeLa cells are 11.9 and 24.8 muM, respectively. SU5416 did not exert such a selective inhibiting effect on Bcl-2 overexpressing HeLa cells. These results suggest that Z24 per os has dose-dependent antitumor and anti angiogenesis pharmacological activity. The higher selectivity of Z24 on Bcl-2 protein and on bFGF other than VEGF signaling path may contribute to its efficiency aga nst tuinor and tumor-associated angiogenesis.