An α-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen

Abstract

Tamoxifen (Tam) is effective for the treatment and prevention of breast cancer. However, it has toxic drawbacks and has limitedduration utility because, over time, human tumours become refractory to Tam. Recently, a new nontoxic peptide, a-fetoproteinderived peptide (AFPep) has been proposed for the treatment and prevention of breast cancer. The purpose of this paper is to determine whether combining AFPep with Tam would increase efficacy and reduce toxicity in experimental models of breast cancer. Low doses of AFPep and Tam were more effective in combination than either agent alone against breast cancer growth in cell culture, in tumour-xenografted mice, and in carcinogen-exposed rats. a-Fetoprotein-derived peptide interfered with Tam-induced uterine hyperplasia in immature mice, and showed no toxic effects. Unlike Tam, AFPep did not inhibit binding of oestradiol (E 2 ) to oestrogen receptor (ER). Thus, these two agents utilise different mechanisms to interfere with ER functionality, yet work cooperatively to reduce breast cancer growth and alleviate Tam's troubling toxicity of uterine hyperplasia and appear to be a rational combination for the treatment of ER-positive breast cancer.

A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy

“…We avoided the use of steroid stimulation so as to preclude any trophic effects of steroids on the MCF-7 cells. In other work (36)(37)(38)(39), as well as in this report, we have shown that E 2 stimulates the growth of MCF-7 and T47D cells; it certainly does not inhibit proliferation. As shown clearly in Fig.…”

Development of an Active Site Peptide Analog of α-Fetoprotein That Prevents Breast Cancer

“…Significantly longer mean tumor-free days and lower tumor multiplicity were observed for AFPep-treated groups (64). AFPep prevented breast cancer in a dose-dependent manner and was effective after treatment durations as short as 10 days or as long as 30 days (65). These studies suggest that AFPep can be used as a chemopreventive agent to reduce the incidence of breast cancer in individuals at high risk for development of this disease.…”

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

“…This obviously gives pause when considering its use for chemoprevention in otherwise healthy women deemed to be at elevated risk for breast cancer. No side effects have as yet been seen with AFPep, and in experimental animals, AFPep has anti-breast cancer effects equivalent to those of tamoxifen (4). This may be due to the fact that AFPep has a mechanism quite different from that of tamoxifen and other SERMs.…”

“…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.…”