Growth inhibition of medullary thyroid carcinoma cells by pyrazolo-pyrimidine derivates

• DOI: 10.1007/bf03349220
• Publication Date: 2014-04-10T14:28:59Z
• Authors: R. Morisi; M. Celano; E. Tosi; S. Schenone; M. Navarra; E. Ferretti; G. Costante; C. Durante; G. Botta; M. D’Agostino; C. Brullo; S. Filetti; M. Botta; D. Russo
• Keywords: 0301 basic medicine; medullary thyroid cancer; mz-crc-i cells; pyrazolopyrimidines; ret; tt cells; Pyrazolopyrimidine; Apoptosis; 03 medical and health sciences; MZ-CRC-I cell; Cell Line, Tumor; Multiple Endocrine Neoplasia Type 1; Humans; Thyroid Neoplasms; Protein Kinase Inhibitors; Medullary thyroid cancer; Proto-Oncogene Proteins c-ret; TT cells; 3. Good health; Pyrimidines; Carcinoma, Medullary; Pyrazoles; Medullary thyroid cancer, TT cells, MZ-CRC-1 cells, RET, pyra; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerases; RET; Medullary thyroid cancer; MZ-CRC-I cells; Pyrazolopyrimidines; RET; TT cells; medullary thyroid carcinoma (MTC); pyrazolopyrimidine derivates; Cell Division

There is no effective treatment for recurrent or metastatic medullary thyroid carcinoma (MTC), a tumor arising from thyroid C-cells commonly presenting an inherited or acquired RET mutation. In this study we examined the sensitivity of two human MTC cell lines to novel pyrazolopyrimidine derivates, able to inhibit src-family tyrosine kinase activity. In TT cells [carrying the multiple endocrine neoplasia (MEN)2A Ret mutation Cys 634Trp] and MZ-CRC-1 cells (carrying the MEN2B RET mutation Met891Thr), one of these compounds, namely Si 34, determined a significant growth inhibitory effect (approximately 90% vs control for TT, 80% vs control for MZ-CRC-1) mainly due to enhanced cell mortality after a 6-day incubation. At concentrations that increased cell mortality, neither biochemical or morphological characteristics of apoptosis were detected in TT and MZCRC- 1 cells treated with Si 34. These results, when confirmed in other in vivo preclinical models, suggest that this novel tyrosine kinase inhibitor may be useful for the treatment of MTC.