Development of a synthetic cyclized peptide derived from alpha-fetoproteinthat prevents the growth of human breast cancer

The peptide, EMTPVNPG, derived from alpha-fetoprotein, inhibits estrogen-st imulated growth of immature mouse uterus and estrogen-dependent proliferati on of human breast cancer cells. However, the biological activities of the peptide diminish over time in storage, even when in the lyophilized state, probably because of peptide aggregation through hydrophobic interaction amo ng monomers. Two analogs of EMTPVNPG were designed with the intent of minim izing aggregation and retaining biological activity during prolonged storag e. EMTOVNOG, where O is 4-hydroxyproline, is a linear peptide generated by substituting 4-hydroxyproline for the two prolines, thereby increasing pept ide hydrophilicity. This analog exhibited a dose-dependent inhibition of es trogen-stimulated growth of immature mouse uterus similar to that of EMTPVN PG (maximal activity at 1 mug/mouse). A second analog, cyclo-(EMTOVNOGQ), a hydrophilic, cyclic analog with increased conformational constraint, was a s potent as the other peptides in its inhibition of estrogen-dependent grow th of immature mouse uterus, and had an expanded effective dose range. Both linear and cyclized hydroxyproline-substituted analogs exhibited indefinit e shelf-life. Furthermore, both analogs inhibited the estrogen-dependent gr owth of MCF-7 human breast cancer growing as a xenograft in SCID mice. Thes e analogs may become significant, novel agents for the treatment of breast cancer.