Breast Cancer Research and Treatment

, Volume 98, Issue 2, pp 133–141

AFPep: an anti-breast cancer peptide that is orally active

  • James A. Bennett
  • Lori DeFreest
  • Ikenna Anaka
  • Hamid Saadati
  • Sujata Balulad
  • Herbert I. Jacobson
  • Thomas T. Andersen
Preclinical study

Summary

Background

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.

Methods

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.

Results

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.

Conclusions

Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.

Keywords

animal models breast cancer oral availability prevention therapy toxicity 

Abbreviations

AFP

alpha-fetoprotein

AFPep

synthetic peptide and active site analog of AFP

DMEM

Dulbecco’s minimal essential medium

ER

estrogen receptor alpha

E2

17β-estradiol

HPLC

high pressure liquid chromatography

i.p.

intraperitoneal administration

MNU

N-methyl-N-nitrosourea

p.o.

oral administration

s.c.

subcutaneous administration

SCID

severe combined immunodeficient mice

SDS PAGE

sodium dodecyl sulfate polyacrylamide gel electrophoresis

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • James A. Bennett
    • 1
    • 4
  • Lori DeFreest
    • 1
  • Ikenna Anaka
    • 2
  • Hamid Saadati
    • 2
  • Sujata Balulad
    • 1
  • Herbert I. Jacobson
    • 1
    • 3
  • Thomas T. Andersen
    • 2
  1. 1.Center for Immunology and Microbial DiseasesAlbany Medical CollegeAlbanyUSA
  2. 2.Center for Cardiovascular SciencesAlbany Medical CollegeAlbanyUSA
  3. 3.Department of Obstetrics, Gynecology and Reproductive SciencesAlbany Medical CollegeAlbanyUSA
  4. 4.Center for Immunology and Microbial Diseases MC-22Albany Medical CollegeAlbanyUSA

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