Enhanced and reversed growth in vitro of a pregnancy-dependent mouse mammary tumor (TPDMT-4) by a gonadotropin-releasing hormone agonist analog.
TPDMT-4 pregnancy-dependent mammary tumors grow continuously in DDD female mice carrying pituitary isografts (PI) ectopically or bearing an s.c. 17 beta-estradiol plus progesterone (EP) pellet. A gonadotropin-releasing hormone (GnRH) agonist, (D-leucyl6, des-glycl-HN2(10), prolyl-ethylamide9) GnRH (TAP-144), was examined for its antitumor activity in these experimental systems. TAP-144 was injected i.p. at doses of 300 and 600 micrograms 6 times weekly, when tumors grew to significant sizes. TAP-144 enhanced tumor growth during the first 2 weeks and subsequently reversed it in a dose-related manner in PI-bearing mice. The agonist did not affect tumor growth in the absence of ovaries in these mice. In ovariectomized mice, TAP-144 enhanced EP pellet-induced tumor growth but never reversed it. In ovariectomized, PI-bearing mice, PAT-144 first enhanced and subsequently reversed tumor regrowth induced by ovarian grafts to a greater extent when commencing it simultaneously with ovarian grafting than 30 days before it. The agonist also exerted the dual effects on TPDMT-4V ovarian-dependent subline tumors in the absence of PI. In TAP-144- treated mice, enhanced tumor growth was related to many solid corpora lutea in ovaries and fully developed mammary glands, but reversed growth was related to atrophied luteal components and mammary glands. The results suggest that TAP-144 enhances tumor growth first via its stimulative action on the pituitary-ovarian axis and causes tumor regression later via its direct inhibitory action on ovaries.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002369:Castration; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016729:Leuprolide; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010053:Ovary / Q000473:pathology / Q000637:transplantation; D010902:Pituitary Gland / Q000637:transplantation; D011374:Progesterone / Q000494:pharmacology
D000970:Antineoplastic Agents; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D016729:Leuprolide