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


METHODS
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.
Parikh
Rahul R
RR
Center for Cardiovascular Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Albany Medical College, Albany, New York 12208, USA.
Gildener-Leapman
Neil
N
Narendran
Amithi
A
Lin
Hung-Yun
HY
Lemanski
Nicole
N
Bennett
James A
JA
Jacobson
Herbert I
HI
Andersen
Thomas T
TT
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites; D005260:Female; D006801:Humans; D015994:Incidence; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D016513:Mice, SCID; D010446:Peptide Fragments / Q000627:therapeutic use*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000477:Alkylating Agents; D010446:Peptide Fragments; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D008770:Methylnitrosourea