title: Effects of treatment with megestrol acetate, aminoglutethimide, or formestane on insulin-like growth factor (IGF) I and II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status in patients with advanced breast cancer.
abstract: The effects of treatment with the aromatase inhibitors aminoglutethimide (AG) and formestane or the synthetic progestin megestrol acetate (MA) on plasma levels of insulin-like growth factor I (IGF-1), IGF-II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status were investigated in 39 patients suffering from advanced breast cancer. Treatment with AG and MA elevated plasma levels of IGF-I by mean values of 27% (n = 15; P < 0.025) and 81% (n = 7; P < 0.025), respectively, whereas treatment with formestane had no effect (n = 13). Treatment with AG increased plasma levels of IGFBP-2, as evaluated by Western blotting (P < 0.01). MA caused a significant reduction in IGFBP-3 protease activity (mean reduction, 69%; P < 0.05). These alterations in plasma IGF-I and IGFBP-3 protease activity were reversed 4 weeks after terminating MA therapy (n = 8; P < 0.025). Taken together, 13 of 15 patients had reduced IGFBP-3 protease activity during treatment with MA compared to the control situation (P < 0.0025). Total levels of IGFBP-3 as measured by RIA were moderately elevated by treatment with MA (mean increase, 19%; P < 0.05), and Western immunoblotting revealed an increase in the amount of intact IGFBP-3 and reduced amounts of IGFBP-3 in the modified form. None of the treatment modalities had any influence on plasma levels of IGF-II. The increase in the plasma IGF-I concentration seen during treatment with MA may be secondary to an increased level of intact IGFBP-3. This could reflect an alteration in IGF availability that contributes to the antitumor effect of MA.
authors.affiliation: Department of Chemical Endocrinology, St. Bartholomew's Hospital, London, United Kingdom.
authors.forename: V J
authors.initials: VJ
authors.lastname: Frost
authors.forename: S I
authors.initials: SI
authors.lastname: Helle
authors.forename: P E
authors.initials: PE
authors.lastname: Lønning
authors.forename: J W
authors.initials: JW
authors.lastname: van der Stappen
authors.forename: J M
authors.initials: JM
authors.lastname: Holly
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000616:Aminoglutethimide / Q000627:therapeutic use; D000735:Androstenedione / Q000031:analogs & derivatives / Q000627:therapeutic use; D047072:Aromatase Inhibitors; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D010450:Endopeptidases / Q000097:blood*; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D019290:Megestrol Acetate / Q000627:therapeutic use; D008875:Middle Aged; D011863:Radioimmunoassay; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D047072:Aromatase Inhibitors; D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins; D000616:Aminoglutethimide; D000735:Androstenedione; D010450:Endopeptidases; C080473:insulin-like growth factor binding protein-3 protease; C014594:formestane; D019290:Megestrol Acetate