Prevention of N-Methyl-N-Nitrosourea–Induced Breast Cancer by α-Fetoprotein (AFP)–Derived Peptide, a Peptide Derived from the Active Site of AFP

Abstract

Purpose: a-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-Nnitrosourea 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 tumorfree 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.

Computational Design and Experimental Discovery of an Antiestrogenic Peptide Derived from α-Fetoprotein

“…More recent reports have shown that AFP has antiestrogenic activity and can inhibit the growth of estrogen dependent cancer. 2,[6][7][8] These data, combined with epidemiological data showing that elevated levels of AFP are associated with a reduced lifetime risk of breast cancer, 7 have led to the suggestion that AFP or analogues thereof may be a useful agent for chemoprevention, as well as for the treatment, of breast cancer. 7,9,10 Festin et al, 11 Eisele et al, 12,13 and Mesfin et al 14 parsed the 70 000 MW AFP into a series of smaller peptides that retained the same antiestrogenic and antibreast cancer activities of the original protein.…”

AFPep, a novel drug for the prevention and treatment of breast cancer, does not disrupt the estrous cycle or fertility in rats

“…Peptide drugs offer attractive options because the large number of possible combinations of amino acids can lead to exquisite specificity and hence the desired efficacy, and because metabolites of peptides are simple amino acids without toxicity. The purpose of this study was to assess the effects of a novel peptide, shown to be useful for the treatment and prevention of breast cancer in animal models (4)(5)(6), on the estrous cycle and reproductive potential in rats prior to initiation of pre-clinical translational studies.…”

“…AFPep is a newly developed peptide demonstrated to have significant activity in the prevention and treatment of breast cancer in experimental models (4)(5)(6) and which is being developed for prevention of breast cancer in women. Effective use of this agent may require its administration to premenopausal and postmenopausal women.…”

“…Notably, while enhancing the anti-tumor activity of tamoxifen (4), AFPep reduces the uterotrophic effect of tamoxifen in mice and so averts a major undesirable side effect of tamoxifen (5). AFPep inhibited the appearance of breast tumors in a chemicallyinduced cancer model (6). Treatment of carcinogen-exposed rats with AFPep yielded significantly more tumor-free days, significantly lower tumor incidence, and significantly decreased tumor burden compared to carcinogen-exposed, but untreated animals.…”

“…There were no indications of toxicity at any time, at any dose (6,30). Other animals (rats and mice) were treated daily for various time periods with therapeutic or preventive (i.e., low) doses of AFPep, and again no evidence of toxicity was seen in any indicator.…”