EFFECTS OF THE LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) ANTAGONIST RAMORELIX (HOE013) AND THE LHRH AGONIST BUSERELIN ON DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY-CARCINOMA - STUDIES WITH SLOW-RELEASE FORMULATIONS

Luteinizing-hormone-releasing hormone (LHRH) agonists and antagonists are antigonadotropic agents for reversible ovarian/testicular suppress ion in gynaecology and in oncology. Pituitary inhibition and suppressi on of the gonadal steroids can be maintained with continuous release r ates from biodegradable implants or microparticles. The effects of cur ative and preventive treatment with slow-release formulations of the L HRH agonist buserelin (implants and microparticles) and the LHRH antag onist ramorelix (hoe013) (microparticles) on dimethylbenz[a]anthracene (DMBA)-induced mammary tumours in rats and the pharmacokinetics of the se 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 o f the peptides. The curative treatment started at the time of full tum our development (76 days after DMBA induction). A single buserelin imp lant injection (3.3 mg peptide) resulted in a dramatic tumour regressi on within 14 days, which was comparable to ovariectomy. It prevented t umour progression for 120 days. Previous studies in rats have shown th at ramorelix microparticles (3.6 mg peptide) have a shorter duration o f action (about 14 days) in suppression of gonadal function when compa red to buserelin microparticles (3.6 mg peptide), where the suppressio n lasted for about 35 days. As expected, a single injection of ramorel ix microparticles (3.6 mg peptide) inhibited tumour progression for on ly 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 tre ated 17 days after DMBA induction before tumour development. Treatment with buserelin implants (3.3 mg peptide) every 56 days or with busere lin microparticles (3.6 mg peptide) every 28 days and the treatment wi th ramorelix microparticles (1.8 mg peptide) every 7 days prevented th e development of tumours. Six weeks after the last injection of ramore lix microparticles a strong tumour progression was seen. There was a c lear correlation between peptide release and tumour inhibition. The im plants and the microparticles were well tolerated, no tissue reaction or side-effects of ramorelix were seen. Treatment of ovariectomized oe stradiol-substituted DMBA-treated rats resulted in a marginal (not sig nificant) inhibition in tumour development. LHRH antagonists in slow-r elease formulations (microparticles or implants) represent a new appro ach 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.