REGULATION OF ENDOMETRIAL CANCER CELL-GROWTH BY INSULIN-LIKE GROWTH-FACTORS AND THE LUTEINIZING-HORMONE-RELEASING HORMONE ANTAGONIST SB-75

The involvement of IGFs in growth regulation of the Ishikawa endometri al tumor cell line and the possible interference of LH-RH analogues wi th a potential autocrine or paracrine loop involving IGFs was evaluate d. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3-fold more potent than IGF-II and 30-fold more potent than insulin, suggesting that the effects of these growth facto rs are mediated by the IGF-I receptor. Ishikawa endometrial cancer cel ls secrete IGF-II, but not IGF-I, and insulin (1 muM) stimulates IGF-I I release. The LH-RH antagonist [AC-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-GnRH (SB-75, CETRORELIX) inhibited basal and IGF-ind uced growth. Moreover, this antagonist almost completely inhibited IGF -II release from Ishikawa cells, while having no significant effect on the number or affinity of IGF-I binding sites. Inhibition of IGF-II r elease occurred at a lower SB-75 concentration than that needed for a reduction in cell number. The ED50 of SB-75 for IGF-II release was 0.3 muM as compared to 1.5 mum concentration which is required for reduct ion in cell number, suggesting that inhibition of growth factor releas e precedes cell growth inhibition. We conclude that the LH-RH antagoni st SB-75 can inhibit the growth of endometrial cancer cells by interfe ring with the autocrine action of IGF-II and also by directly inhibiti ng the growth-stimulatory effects of IGFs, probably through effects on a post-receptor mechanism.