Prevention of N-methyl-N-nitrosourea-induced breast cancer by α-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP

Rahul R. Parikh, Neil Gildener-Leapman, Amithi Narendran, Hung Yun Lin, Nicole Lemanski, James A. Bennett, Herbert I. Jacobson, Thomas T. Andersen

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Purpose: α-Fetoprotein (AFP) is a protein of pregnancy associated with a decrease in lifetime risk of breast cancer in parous women. A synthetic, cyclic nonapeptide has been developed that mimics the antioncogenic active site of AFP. To test the hypothesis that the AFP-derived peptide (AFPep) can prevent breast cancer, the N-methyl-N-nitrosourea-induced breast cancer model was used in rats. Experimental Design: AFPep was given daily by injection beginning 10 days after N-methyl-N-nitrosourea treatment and continued for 23 days (a time designed to mimic pregnancy) or for other times to assess efficacy as a function of drug duration. Tumor incidence, multiplicity, and latency were noted as end points. At necropsy, pathology analysis of tumors and major organs were obtained. Results: AFPep prevented cancer in a dose-dependent fashion. Significantly longer mean tumor-free days (P <0.02), lower tumor incidence (P = 0.004), and lower tumor multiplicity were observed for AFPep-treated groups. No evidence of host toxicity as measured by body weight, cage activity, fur texture, and organ weights (liver, uterus, heart, kidney, and spleen) were found in animals treated with AFPep. Mechanistic studies using transplantable human breast cancer xenografts showed that the peptide interfered with estrogen-dependent breast cancer growth inhibited the phosphorylation of the estrogen receptor and activated phosphorylation of p53. Conclusions: AFPep is a well-tolerated, mechanistically novel, chemopreventive agent in models of breast cancer and warrants further development for the prevention and treatment of this disease in humans.

Original languageEnglish
Pages (from-to)8512-8520
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number23
DOIs
Publication statusPublished - Dec 1 2005
Externally publishedYes

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Fetal Proteins
Methylnitrosourea
Catalytic Domain
Breast Neoplasms
Peptides
Neoplasms
Phosphorylation
Pregnancy Proteins
Organ Size
Incidence
Heterografts
Estrogen Receptors
Uterus
Estrogens
Research Design
Spleen
Body Weight
Pathology
Kidney
Pregnancy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Prevention of N-methyl-N-nitrosourea-induced breast cancer by α-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP. / Parikh, Rahul R.; Gildener-Leapman, Neil; Narendran, Amithi; Lin, Hung Yun; Lemanski, Nicole; Bennett, James A.; Jacobson, Herbert I.; Andersen, Thomas T.

In: Clinical Cancer Research, Vol. 11, No. 23, 01.12.2005, p. 8512-8520.

Research output: Contribution to journalArticle

Parikh, Rahul R. ; Gildener-Leapman, Neil ; Narendran, Amithi ; Lin, Hung Yun ; Lemanski, Nicole ; Bennett, James A. ; Jacobson, Herbert I. ; Andersen, Thomas T. / Prevention of N-methyl-N-nitrosourea-induced breast cancer by α-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 23. pp. 8512-8520.
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abstract = "Purpose: α-Fetoprotein (AFP) is a protein of pregnancy associated with a decrease in lifetime risk of breast cancer in parous women. A synthetic, cyclic nonapeptide has been developed that mimics the antioncogenic active site of AFP. To test the hypothesis that the AFP-derived peptide (AFPep) can prevent breast cancer, the N-methyl-N-nitrosourea-induced breast cancer model was used in rats. Experimental Design: AFPep was given daily by injection beginning 10 days after N-methyl-N-nitrosourea treatment and continued for 23 days (a time designed to mimic pregnancy) or for other times to assess efficacy as a function of drug duration. Tumor incidence, multiplicity, and latency were noted as end points. At necropsy, pathology analysis of tumors and major organs were obtained. Results: AFPep prevented cancer in a dose-dependent fashion. Significantly longer mean tumor-free days (P <0.02), lower tumor incidence (P = 0.004), and lower tumor multiplicity were observed for AFPep-treated groups. No evidence of host toxicity as measured by body weight, cage activity, fur texture, and organ weights (liver, uterus, heart, kidney, and spleen) were found in animals treated with AFPep. Mechanistic studies using transplantable human breast cancer xenografts showed that the peptide interfered with estrogen-dependent breast cancer growth inhibited the phosphorylation of the estrogen receptor and activated phosphorylation of p53. Conclusions: AFPep is a well-tolerated, mechanistically novel, chemopreventive agent in models of breast cancer and warrants further development for the prevention and treatment of this disease in humans.",
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AU - Gildener-Leapman, Neil

AU - Narendran, Amithi

AU - Lin, Hung Yun

AU - Lemanski, Nicole

AU - Bennett, James A.

AU - Jacobson, Herbert I.

AU - Andersen, Thomas T.

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