TT-232: a somatostatin structural derivative as a potent antitumor drug candidate.
TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) has been developed as an antitumor somatostatin analog. TT-232 has no growth hormone release inhibitory effect and does not inhibit the secretion of gastric acid. This analog induces apoptosis in and exerts pronounced antiproliferative effects on various human tumors (colon, pancreas, lymphoma, leukemia, melanoma, hepatoma) cell lines. The growth of human xenografts (prostate, breast carcinoma, lymphoma, melanoma) and animal tumors (colon-26, P-388, S-180, B16, MXT) was inhibited by TT-232 (dose range: 30-750 microg/kg/day) in 54-98% of cases. Continuous long-term infusion proved to be the most effective way of administration. TT-232 combined with decarbazine or etoposide treatment enhanced the antitumor activity of these drugs on human melanoma and lymphoma xenografts, respectively. Regarding the mode of action, TT-232 activates cell cycle inhibitors via SSTR receptors, inhibits tyrosine kinases through interfering with the proliferative signaling cascades, and interacts with an intracellular receptor and an enzyme involved in glycolysis causing translocation of this enzyme to the nucleus, thus inducing apoptosis. TT-232 may be a promising candidate in the therapy of human malignancies.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin; D005047:Etoposide; D003606:Dacarbazine