A TUMOR-SELECTIVE SOMATOSTATIN ANALOG (TT-232) WITH STRONG IN-VITRO AND IN-VIVO ANTITUMOR-ACTIVITY

We report a series of new in vitro and in vivo data proving the select ive antitumor activity of our somatostatin structural derivative, TT-2 32, In vitro, it inhibited the proliferation of 20 different human tum or cell lines in the range of 50-95% and induced a very strong apoptos is, In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts, Tre atment of MDA-MB-231 human breast cancer xenografted in mice with low submaximal doses of TT-232 [0.25 and 0.5 mg/kg of body weight (b,w,)] caused an average 80% decrease in the tumor volume resulting in 30% tu mor-free animals surviving for longer than 200 days, Treatment of pros tate tumor (PC-3) xenografted animals with 20 mg/kg of b.w. of TT-232 for 3 weeks resulted in 60% decrease in tumor volume and 100% survival even after 60 days, while 80% of nontreated animals perished, We have demonstrated that TT-232 did not bind to the membrane preparation of rat pituitary and cortex and had no antisecretory activity, TT-232 was not toxic at a dose of 120 mg/kg of b,w, in mice. Long-term incubatio n (24 h) of tumor cells with TT-232 caused significant inhibition of t yrosine kinases in good correlation with the apoptosis-inducing effect , The level of p53 or KU86 did not change following TT-232 treatment, suggesting a p53-independent apoptotic effect, Preincubation of human breast cancer cells (MDA-MB-453) with TT-232 for 2 h decreased the gro wth factor receptor autophosphorylation, All of these data suggest tha t TT-232 is a promising and selective antitumor agent.