A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity
Abstract
We report a series of new in vitro and in vivo data proving the selective antitumor activity of our somatostatin structural derivative, TT-232.
In vitro, it inhibited the proliferation of 20 different human tumor cell lines in the range of 50-95% and induced a very strong apoptosis.
In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts.
Treatment 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% tumor-free animals surviving for longer than 200 days.
Treatment of prostate 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 incubation (24 h) of tumor cells with TT-232 caused significant inhibition of tyrosine 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 growth factor receptor autophosphorylation.
All of these data suggest that TT-232 is a promising and selective antitumor agent.
See also:
- Somatostatin in oncology, the overlooked evidences;
- The Di Bella Method (A Fixed Part - Cyclophosphamide and/or Hydroxyurea tablets, one or two per day).