SOMATOSTATIN-14 AND ITS ANALOG OCTREOTIDE EXERT A CYTOSTATIC EFFECT ON GH(3) RAT PITUITARY-TUMOR CELL-PROLIFERATION VIA A TRANSIENT G0 G1 CELL-CYCLE BLOCK/

Somatostatin (SRIF) and its analogs exert potent inhibitory effects on hormonal hypersecretion. In addition, they have been demonstrated to inhibit the proliferation of various cell Lines as well, as the growth of some endocrine tumors in vivo. To evaluate the action of SRIF and its analog octreotide on the proliferation and cell cycle kinetics of endocrine cells, we investigated their effect on GH(3) rat pituitary t umor cells, a GH-producing cell line. Using flaw cytometric DNA. analy sis with propidium iodide staining, we found that octreotide inhibits the proliferation of synchronized GH(3) cells, achieving a maximal red uction, compared to controls, of 19.4 +/- 5.3% and 22.4 +/- 5.1% with 100 ng/ml and 1000 ng/ml octreotide, respectively (P < 0.05). This eff ect was demonstrated to be due to a block in progression from the G0/G 1 phase to the S phase of the cell cycle. This was most evident after 24 h of exposure to 100 ng/ml octreotide, at which time there was a 7. 1 +/- 1.4% increase in cells in G0/G1 (P < 0.01) and a 6.6 +/- 1.3% de crease in cells in S phase IP < 0.01). However, unless octreotide was replenished, this effect was transient and overcome by 36-48 h. No apo ptosis was seen, and trypan blue studies confirmed that cell death by necrosis did not occur. A single exposure to native SRIF-14 had little effect, hut a G0/G1 cell cycle block and inhibition of proliferation were seen if SRIF was regularly replenished. We conclude that SRIF and octreotide exert a cytostatic effect on GH(3) cells by causing a part ial G0/G1 cell cycle black. These findings suggest that the actions of SRIF and octreotide occur through signal transduction pathways that a ct predominantly on downstream regulators.