Growth inhibitory effect of the somatostatin structural derivative (TT-232) on leukemia models.
TT-232 is a structural derivative of the natural signal inhibitory peptide somatostatin, with selective antiproliferative and anti-inflammatory properties. TT-232 activates SSTR receptors (primarily the SSTR-1), which leads to irreversible cell cycle arrest, followed by secondary induction of apoptosis. TT-232 has passed phase I clinical trials without toxicity and significant side-effects. We examined the antiproliferative effect in vitro and the antitumor effect in vivo of TT-232 on leukemia cell lines. During in vivo experiments, we evaluated the therapeutic efficacy of TT-232 in various long-term administration routes; traditional injection versus infusion treatment via an inserted Alzet minipump on P-388 mice and HL-60 human leukemia models. Treatment with TT-232 started after development of the disease. In vitro, TT-232 inhibited the proliferation of P-388 mice lymphoid cells and HL-60 human promyelocytic leukemia cells in the range of 46%-97% with 24-hour treatment and 82%-100% with 48-hour treatment. Cells were treated with 30 microg/ml and 60 microg/ml dose of TT-232. With the same in vivo models, the best results were achieved when TT-232 was applied by infusion treatments. The infusion treatment with TT-232 produced 50%-80% inhibition of growth and resulted in 20%-40% long-term and leukemia-free survivors. TT-232 showed dose-, time- and administration mode-dependent antileukemia activity in vitro and in vivo, both on rodent and human models. Our results suggest that TT-232 is a promising new antileukemia agent.
Tejeda
M
M
National Institute of Oncology, Department of Experimental Pharmacology, Budapest, Hungary. mtejeda.farm@oncol.hu
Gaál
D
D
Csuka
O
O
Kéri
Gy
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D051379:Mice; D008808:Mice, Inbred CBA; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin