Luteinizing-hormone-releasing hormone (LHRH) agonists and antagonists are antigonadotropic agents for reversible ovarian/testicular suppression in gynaecology and in oncology. Pituitary inhibition and suppression of the gonadal steroids can be maintained with continuous release rates from biodegradable implants or microparticles. The effects of curative and preventive treatment with slow-release formulations of the LHRH agonist buserelin (implants and microparticles) and the LHRH antagonist ramorelix (hoe013) (microparticles) on dimethylbenz[a]anthracene(DMBA)-induced mammary tumours in rats and the pharmacokinetics of these formulations are described. In addition, direct effects of the LHRH antagonist ramorelix on tumour growth were studied. The release rates of the implants (polylactide-glycolide 75:25) and the microparticles (polylactide-glycolide 50:50) were calculated from urinary excretion of the peptides. The curative treatment started at the time of full tumour development (76 days after DMBA induction). A single buserelin implant injection (3.3 mg peptide) resulted in a dramatic tumour regression within 14 days, which was comparable to ovariectomy. It prevented tumour progression for 120 days. Previous studies in rats have shown that ramorelix microparticles (3.6 mg peptide) have a shorter duration of action (about 14 days) in suppression of gonadal function when compared to buserelin microparticles (3.6 mg peptide), where the suppression lasted for about 35 days. As expected, a single injection of ramorelix microparticles (3.6 mg peptide) inhibited tumour progression for only 14 days. This short action is due to a different release profile of the ramorelix microparticles and the different specific activities of peptides incorporated. In the preventive experiments animals were treated 17 days after DMBA induction before tumour development. Treatment with buserelin implants (3.3 mg peptide) every 56 days or with buserelin microparticles (3.6 mg peptide) every 28 days and the treatment with ramorelix microparticles (1.8 mg peptide) every 7 days prevented the development of tumours. Six weeks after the last injection of ramorelix microparticles a strong tumour progression was seen. There was a clear correlation between peptide release and tumour inhibition. The implants and the microparticles were well tolerated, no tissue reaction or side-effects of ramorelix were seen. Treatment of ovariectomized oestradiol-substituted DMBA-treated rats resulted in a marginal (not significant) inhibition in tumour development. LHRH antagonists in slow-release formulations (microparticles or implants) represent a new approach in treatment of hormone-dependent tumours because of the immediate onset of gonadal function and the increased drug efficacy due to the controlled release from biodegradable microparticles.
The effects of the progesterone antagonists (antiprogestins) onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis were studied in intact female rats. Endometriosis was induced by transplanting homologous endometrium to the parietal peritoneum of the abdominal wall (location A) and to the mesentery of the small intestine (location B). The animals were treated daily for 4 weeks at doses of 0.4 and 2.0 mg onapristone or ZK 136 799. The growth of the endometriosis-like foci was measured with a calliper during both pre- and post-treatment laparotomy. Both antiprogestins exerted inhibitory effects on the growth of the endometriosis-like foci in terms of complete remission. A 40 and 50% remission of endometriosis was observed at each location after the administration of 2.0 mg onapristone, whereas 50 and 63% (location A) and 50 and 75% (location B) remissions were found after the administration of 0.4 and 2.0 mg of ZK 136 799 respectively. ZK 136 799 was also more potent than onapristone in growth inhibition (85 versus 48% for location B) in animals with persistent endometriosis. Growth inhibition of the endometriosis-like foci was confirmed by histology and immunohistochemical staining of the proliferating cell nuclear antigen. The antiprogestins caused a reduction in glandular and luminal epithelial cells in the ectopic endometrium. Both antiprogestins tended to cause a decrease in uterine weight. Unlike the inhibitory effects in the ectopic endometrium, both onapristone and ZK 136 799 exhibited some stimulatory effects on the epithelial cells within the eutopic endometrium. Serum 17 beta-oestradiol concentrations did not vary significantly among the different treatment groups. No antiglucocorticoid effect of the antiprogestins was observed at either dose. This study indicates that the antiprogestins onapristone and ZK 136 799 exhibit antiproliferative effects in the ectopic but not the eutopic endometrium via mechanisms which remain to be established. The better efficacy of ZK 136 799 is more likely caused by its higher antiprogestagenic activity than its partial androgenic activity. These findings may be a further indication of the future potential of antiprogestins such as onapristone and ZK 136 799 in the treatment of endometriosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.