Effects of the luteinizing-hormone-releasing hormone (LHRH) antagonist ramorelix (hoe013) and the LHRH agonist buserelin on dimethylbenz[]anthracene-induced mammary carcinoma: studies with slow-release formulations.

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.