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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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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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Acknowledgements

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).

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Authors and Affiliations

  1. Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY, USA

    James A. Bennett, Lori DeFreest, Sujata Balulad & Herbert I. Jacobson

  2. Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA

    Ikenna Anaka, Hamid Saadati & Thomas T. Andersen

  3. Department of Obstetrics, Gynecology and Reproductive Sciences, Albany Medical College, Albany, NY, USA

    Herbert I. Jacobson

  4. Center for Immunology and Microbial Diseases MC-22, Albany Medical College, Albany, NY, 12208, USA

    James A. Bennett

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  1. James A. Bennett
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  2. Lori DeFreest
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  3. Ikenna Anaka
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  4. Hamid Saadati
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  5. Sujata Balulad
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  6. Herbert I. Jacobson
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  7. Thomas T. Andersen
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Correspondence to James A. Bennett.

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Bennett, J.A., DeFreest, L., Anaka, I. et al. AFPep: an anti-breast cancer peptide that is orally active. Breast Cancer Res Treat 98, 133–141 (2006). https://doi.org/10.1007/s10549-005-9140-5

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  • DOI: https://doi.org/10.1007/s10549-005-9140-5

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