d-phenylalanyl-cysteinyl-tyrosyl-tryptophyl-lysyl-cysteinyl-threoninamide and Colonic-Neoplasms

The somatostatin analogue TT-232, containing a five residue ring structure, has a strong antitumour activity both in vitro and in vivo. This peptide has no effect on growth hormone (GH) release, but exhibits a remarkable tyrosine kinase inhibitory effect and induced apoptosis. We studied the effect of TT-232 in different routes of administration and treatment schedules on various types of mouse tumour models. The infusion treatment with inserted Alzet osmotic minipumps proved to be superior to both twice daily subcutaneous (s.c.) or intravenous (i.v.) injections in a 2 weeks period. In the case of S-180 tumour the infusion treatment resulted in 77-100% tumour growth inhibition and in 40-60% of mice long-term and tumour-free survivors. With the P-388sc tumour the infusion of TT-232 resulted in 20-40% of animals long-term and tumour-free survivors and in 76-100% tumour growth inhibition. In the very aggressive Colon-26 (C-26) and MXT, the TT-232 treatment resulted in 71-75% tumour growth inhibition and increased survival time by about 50%.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Growth Hormone; Injections, Intravenous; Injections, Subcutaneous; Leukemia P388; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Peptides, Cyclic; Sarcoma 180; Somatostatin; Survival Rate; Tumor Cells, Cultured

Somatostatin has been demonstrated to activate phosphotyrosine phosphatases (PTPases) in pancreatic cells. In this work we studied the effect of a tumor-selective somatostatin structural derivative, TT2-32, on the PTPase activity in the SW620 human colon tumor cell line. TT2-32 caused a strong inhibition of cell proliferation. In response to TT2-32 we found a rapid and sustained increase (5-30 min) in PTPase activity showing two maxima at 0.1 and 30 microM concentrations, respectively. During short-term incubation tyrosine kinase activity was much less affected by TT2-32. TT2-32-induced activation of PTPases may be an important early step in the signaling cascade in the inhibition of cell proliferation in colon carcinomas.

Topics: Amino Acid Sequence; Antineoplastic Agents; Cell Division; Colonic Neoplasms; Enzyme Activation; Humans; Molecular Sequence Data; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Signal Transduction; Somatostatin; Tumor Cells, Cultured