Suppression of Tyrosine Kinase Activity Inhibits[ 3H]Thymidine Uptake in Cultured Human Pituitary Tumor Cells1

Tyrosine kinases are involved in the phosphorylation of proteins that regulate cell growth and proliferation. The mitogenic effect of several growth factors requires tyrosine kinase activity of their receptors. The effect of inhibition of tyrosine kinase activity on thymidine uptake 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[ 3H]thymidine to be investigated in the experiments. Genestein and MDHC both potently inhibited thymidine uptake into these tumors, with a mean inhibition by 74 μmol/L genestein of 61.96± 18.96% (±sd inhibition of basal), by 740 μmol/L genestein of 92.65 ± 8.59%, and by 100 μmol/L MDHC of 93.84 ± 3.85%. The 7 pituitary adenomas were all large with suprasellar extension and secreted interleukin-6 in vitro. They included 2 prolactinomas, 1 somatotropinoma, 1 mammosomatropinoma, and 3 clinically nonfunctioning adenomas. Epidermal growth factor stimulated thymidine uptake in 2 of the 3 clinically nonfunctioning adenomas studied, and this stimulation was inhibited by genestein. Both of these tumors released FSH in cell culture and are probably silent gonadotropinomas. The growth stimulatory effect of conditioned medium from human pituitary cell culture on GH3 cells was inhibited by both genestein and MDHC. We conclude that tyrosine kinase activity is crucial for the integrity and growth of pituitary adenomas in culture. Growth factors released by pituitary adenomas potentially may maintain and promote tumor growth by stimulating tyrosine kinase activity.