SUPPRESSION OF TYROSINE KINASE-ACTIVITY INHIBITS [H-3] THYMIDINE UPTAKE IN CULTURED HUMAN PITUITARY-TUMOR CELLS

Tyrosine kinases are involved in the phosphorylation of proteins that regulate cell growth and proliferation. The mitogenic effect of severa l growth factors requires tyrosine kinase activity of their receptors. The effect of inhibition of tyrosine kinase activity on thymidine upt ake into cultured human pituitary adenoma cells was studied using two inhibitors, genestein and methyl-2,3-dihydroxycinnamate (MDHC). Of 33 pituitary adenomas, 7 incorporated sufficient [H-3]thymidine to be inv estigated in the experiments. Genestein and MDHC both potently inhibit ed thymidine uptake into these tumors, with a mean inhibition by 74 mu mol/L genestein of 61.96 +/- 18.96% (+/-SD inhibition of basal), by 7 40 mu mol/L genestein of 92.65 +/- 8.59%, and by 100 mu mol/L MDHC of 93.84 +/- 3.85%. The 7 pituitary adenomas were all large with suprasel lar extension and secreted interleukin-6 in vitro. They included 2 pro lactinomas, 1 somatotropimoma, 1 mammosomatropinoma, and 3 clinically nonfunctioning adenomas. Epidermal growth factor stimulated thymidine uptake in 2 of the 3 clinically nonfunctioning adenomas studied, and t his stimulation was inhibited by genestein. Both of these tumors relea sed FSH in cell culture and are probably silent gonadotropinomas. The growth stimulatory effect of conditioned medium from human pituitary c ell culture on GH, cells was inhibited by both genestein and MDHC. We conclude that tyrosine kinase activity is crucial for the integrity an d growth of pituitary adenomas in culture. Growth factors released by pituitary adenomas potentially may maintain and promote tumor growth b y stimulating tyrosine kinase activity.