Alpha-fetoprotein-derived antiestrotrophic octapeptide

Alpha-fetoprotein (AFP) is a major serum protein produced during fetal deve lopment. Experimental findings suggest that AFP has antiestrotrophic activi ty and that it can be developed as a therapeutic agent to treat existing es trogen-dependent breast cancer or to prevent premalignant foci from develop ing into breast cancer. The antiestrotrophic activity of AFP was reported t o be localized to a peptide consisting of amino acids 447-480, a 34-mer pep tide termed P447. A series of parsings and substitutions of amino acids in the P447 sequence was intended to identify the shortest analog which retain ed antiestrotrophic activity. Peptides related to P447 were generated using solid phase peptide synthesis. Several shorter peptides, including an 8-me r called P472-2 (amino acids 472-479, peptide sequence EMTPVNPG), retained activity, whereas peptides shorter than eight amino acid residues were inac tive. The dose-related antiestrotrophic activity of AFP-derived peptides wa s determined in an immature mouse uterine growth assay that measures their ability to inhibit estradiol-stimulated uterine growth. In this assay, the maximal inhibitory activities exhibited by peptide P472-2 (49%), by peptide P447 (45%), and by intact AFP (35-45%) were comparable. The octapeptide P4 72-2 was also active against estradiol-stimulated growth of T47D human brea st cancer cells in culture. These data suggest that peptide P472-2 is the m inimal sequence in AFP, which retains the antiestrotrophic activity found w ith the full-length molecule. The synthetic nature and defined structure of this 8-mer peptide suggest that it can be developed into a new drug which opposes the action of estrogen, perhaps including the promotional effects o f estradiol in the development of human breast cancer. (C) 2000 Elsevier Sc ience B.V. All rights reserved.