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 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.
Joint Research Organization, Hungarian Academy of Sciences, Budapest, Hungary.
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G
Kéri
J
J
Erchegyi
A
A
Horváth
I
I
Mezõ
M
M
Idei
T
T
Vántus
A
A
Balogh
Z
Z
Vadász
G
G
Bökönyi
J
J
Seprõdi
I
I
Teplán
O
O
Csuka
M
M
Tejeda
D
D
Gaál
Z
Z
Szegedi
B
B
Szende
C
C
Roze
H
H
Kalthoff
A
A
Ullrich
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin; D011505:Protein-Tyrosine Kinases