ANTITUMOR EFFECT OF A GONADOTROPIN-RELEASING-HORMONE ANTAGONIST (MI-1544) AND ITS CONJUGATE ON HUMAN BREAST-CANCER CELLS AND THEIR XENOGRAFTS

Our gonadotropin-releasing hormone (GnRH) antagonist analogue MI-1544 ([Ac-D-Trp(1,3),D-Cpa(2),D-Lys(6),D-Ala(10)]GnRH) was developed as a p otential contraceptive material, because it decreased the luteinizing hormone level without unfavourable side-effects. The antagonist was co valently bound to poly[Lys-(Ac-Glu(0.96)-DL-Ala(3.1))] (AcEAK) - a bra nched polypeptide having a polylysine backbone - resulting in a MI-154 4-AcEAK conjugate. According to our in vitro experiments the MI-1544 i nduced a 33%-35% decrease in cell numbers of MCF-7 and MDA-MB-231 huma n breast cancer cell lines at a dose of 30 mu M. The biodegradable pol ymeric 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, appl ied twice daily s.c., inhibited the growth of oestrogen-sensitive and -insensitive xenografts by 65% and 30% respectively. This effect was p otentiated (70%) in both types of xenografts by the presence of the po lymeric carrier in the conjugate; however, the carrier by itself did n ot cause tumour growth inhibition. The polymeric polypeptide carrier i s supposed to increase the stability of the GnRH antagonist and to pre vent the rapid excretion of the covalently bound peptide molecule. The antagonist and its conjugate may have various direct and indirect eff ects on breast cancer cells and, as a consequence, the new GnRH antago nist conjugates are suitable for treating an extended range of breast cancers.