Our
gonadotropin-releasing hormone (
GnRH) antagonist analogue
MI-1544 ([Ac-D-Trp1,3,D-Cpa2,D-Lys6,D-Ala10]
GnRH) was developed as a potential
contraceptive material, because it decreased the
luteinizing hormone level without unfavourable side-effects. The antagonist was covalently bound to poly[Lys-(Ac-Glu0.96-DL-Ala3.1)] (AcEAK)-a branched
polypeptide having a
polylysine backbone--resulting in a MI-1544-AcEAK conjugate. According to our in vitro experiments the
MI-1544 induced a 33%-35% decrease in cell numbers of MCF-7 and MDA-MB-231 human
breast cancer cell lines at a dose of 30 microM. The biodegradable polymeric carrier, AcEAK, alone inhibited cell proliferation by only 13%-15%, while the MI-1544-AcEAK conjugate, applied at the same dose, was capable of producing 45%-50% inhibition of cell proliferation. Our in vivo experiments using immunosuppressed mice showed that
MI-1544, applied twice daily s.c., inhibited the growth of oestrogensensitive and -insensitive xenografts by 65% and 30% respectively. This effect was potentiated (70%) in both types of xenografts by the presence of the polymeric carrier in the conjugate; however, the carrier by itself did not cause tumour growth inhibition. The polymeric
polypeptide carrier is supposed to increase the stability of the
GnRH antagonist and to prevent the rapid excretion of the covalently bound
peptide molecule. The antagonist and its conjugate may have various direct and indirect effects on
breast cancer cells and, as a consequence, the new
GnRH antagonist conjugates are suitable for treating an extended range of breast
cancers.