Luteinizing hormone-releasing hormone antagonists interfere with autocrine and paracrine growth stimulation of MCF-7 mammary cancer cells by insulin-like growth factors.
Several studies have supported the idea that LH-releasing hormone (LHRH) antagonists have a direct effect on mammary tumor cells. In this study, we have evaluated the potential role of the insulin-like growth factors (IGFs) on the growth of MCF-7 mammary tumor cells and the effect of LHRH analogs on IGF action. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3 times more potent than IGF-II and 30 times more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. IGFs released by MCF-7 cells were measured by specific RIA after acid extraction and chromatography, so as to avoid the interference of IGF-binding proteins. MCF-7 cells secreted IGF-II, but not IGF-I. Estradiol (10(-9) mol/L) stimulated IGF-II release; this release preceded the effect of estradiol on cell growth. The LHRH antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10] LHR H (SB-75, CETRORELIX) inhibited basal, estrogen-induced, and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from MCF-7 cells. This effect preceded the inhibition of tumor cell growth. We conclude that a LHRH antagonist can inhibit the growth of breast tumors by interfering with the autocrine action of IGF-II and by directly inhibiting the growth stimulatory effect of IGFs.
Hershkovitz
E
E
Clinical Biochemistry Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center of Kupat Holim, Beer-Sheva, Israel.
Marbach
M
M
Bosin
E
E
Levy
J
J
Roberts
C T
CT
LeRoith
D
D
Schally
A V
AV
Sharoni
Y
Y
D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002064:Buserelin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D011863:Radioimmunoassay; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007328:Insulin; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C062876:cetrorelix; D002064:Buserelin