AFPep: an anti-breast cancer peptide that is orally active
- 135 Downloads
We have synthesized a cyclic nonapeptide (AFPep) that is effective, after being administered by parenteral routes, for the treatment or the prevention of breast cancer. To test the hypothesis that AFPep remains safe and efficacious after oral administration, three different whole-animal bioassays were utilized, and the mechanism by which AFPep functions was investigated.
Using a human breast cancer xenograft model in mice for therapeutic activity, a carcinogen-induced breast cancer model in rats for prevention efficacy, and a mouse uterus growth inhibition model of anti-estrogenic activity, AFPep was administered by oral gavage (p.o.) and its effects compared to those following intraperitoneal (i.p.) and subcutaneous (s.c.) administration. Toxicity studies evaluated body weights and organ weights in mice and rats receiving AFPep. Preliminary mechanistic studies were carried out in T47D human breast cancer cells growing in culture and evaluated the effect of AFPep on estrogen-stimulated cell growth, phosphorylation of the estrogen receptor (ER), and on level of ER-related kinases.
Orally administered AFPep stopped the growth of human tumor xenografts in mice, decreased the incidence and multiplicity of breast cancers in carcinogen-exposed rats, and inhibited the estrogen-stimulated growth of mouse uteri. In each of these systems, orally administered AFPep produced an effect similar to that obtained for AFPep administered by either i.p or s.c. routes. In rodents, no evidence of toxicity was seen for the peptide, even at very high doses. In culture, AFPep inhibited the estrogen-stimulated growth, but not the basal growth, of T47D cells, and it inhibited the estrogen-stimulated phosphorylation of Serine 118 in the ER of these cells, which was not explainable by early changes in ER-related kinases.
Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.
Keywordsanimal models breast cancer oral availability prevention therapy toxicity
synthetic peptide and active site analog of AFP
Dulbecco’s minimal essential medium
estrogen receptor alpha
high pressure liquid chromatography
severe combined immunodeficient mice
- SDS PAGE
sodium dodecyl sulfate polyacrylamide gel electrophoresis
Unable to display preview. Download preview PDF.
This work was supported by the NIH (R01 CA102540), the Department of Defense (DAMD17–02–1–0269) and the Susan B. Komen Foundation (DISS-0201775).
- 5.DeFreest LA, Mesfin FB, Joseph L, McLeod DJ, Stallmer A, Reddy S, Balulad SS, Jacobson HI, Andersen TT, Bennett JA, Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization J Pept Res 63:409–419, 2004PubMedCrossRefGoogle Scholar
- 6.Kates SA, Sole NA, Beyermann M, Barany G, Albericio F, Optimized preparation of deca(L-alanyl)-L-valinamide by 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis on polyethylene glycol-polystyrene (PEG-PS) graft supports, with 1,8-diazobicyclo [5.4.0]-undec-7-ene (DBU) deprotection Pept Res 9:106–113, 1996PubMedGoogle Scholar
- 16.Chaabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P, Antineoplastic agents In: Hardman JG, Lumbird LE, Goodnam-Gilman A, (eds) The Pharmacological Basis of Therapeutics McGraw Hill NY 2001 pp 1389–1459Google Scholar
- 17.Goetz MP, Erlichman C, Loprinzi CL, Pharmacology of endocrine manipulations In: DeVita VT, Hellman S, Rosenberg AS, (eds.) Cancer. Principles and Practice of Oncology Lipincott Williams & Wilkins NY 2005 pp. 457–470Google Scholar