AFPep explained

AFPep (alpha fetoprotein peptide) is an orally-active, cyclic, 9-amino acid, peptide with a molecular weight of 969 daltons and is derived from the anti-oncogenic active site (residues 472–479) of alpha fetoprotein (AFP).[1] Using the standard amino acid abbreviations, AFPep has the sequence cyclo(EKTOVNOGN), where O is hydroxyproline. This peptide has been shown in experimental animal models to be efficacious in the prevention and treatment of ER+ breast cancer.[2]

Biological activity

Background

Multiple births by a woman are strongly associated with a lower risk of developing breast cancer later in her life.[3] One of the contributing factors for this association appears to be the alpha fetoprotein (AFP) produced by the fetal liver, which crosses the placenta and enters into the maternal circulation.[4] Pregnancy-associated protection from breast cancer is directly proportional to level of exposure to AFP.[5] Furthermore, it has been demonstrated that tumor growth can be inhibited by AFP in animal models of breast cancer.[6] [7] It is speculated that AFP may induce apoptosis in pre-malignant breast tissue cells which would have later developed into malignancies.[3]

Anti cancer effects

Through mimicking the effects of AFP, AFPep inhibits the proliferation of estrogen receptor-positive human breast cancer cells growing in culture.[8] It is also able to inhibit the estrogen stimulated growth of human breast cancer cells growing as xenografts in immunodeficient mice.[8] According to a recent study, AFPep prevents the development of carcinogen-induced breast cancer in an animal model.[9] Hence AFPep may have utility for preventing or treating estrogen receptor-positive breast cancer.

Mechanism of action

AFPep inhibits estrogen-stimulated growth of immature mouse uterus and thus is antiestrogenic. In culture, AFPep inhibits the estrogen induced proliferation of T47D cells but has no effect on the basal growth.[10] AFPep also inhibits phosphorylation of the estrogen receptor and activates the phosphorylation of p53.[10]

AFPep has been shown to bind the heat shock protein Hsp72.[11] Hsp72 together with Hsp90 form a heterocomplex with the estrogen receptor. Hence AFPep through interaction with Hsp72 controls the ligand binding and transcriptional activation of the estrogen receptor.

Combination therapy with tamoxifen

AFPep increases the efficacy and decreases the toxicities of tamoxifen. Tamoxifen has been a very effective drug for the treatment of estrogen receptor-positive breast cancer. But tamoxifen has certain toxicities and side effects[12] [13] [14] such as uterine hyperplasia which can lead to endometrial cancer. Moreover, some breast cancers acquire resistance to tamoxifen during the course of treatment and few are totally resistant to it. It has been established that AFPep when used in combination with tamoxifen, reduces the uterine hyperplasia and increases the antitumour effects of tamoxifen. A rational combination of AFPep and tamoxifen may prove to be a better chemopreventive or chemotherapeutic approach against estrogen receptor-positive breast cancer.[2]

Route of administration

AFPep active whether administered intraperitoneally, subcutaneously or orally.[10]

Notes and References

  1. Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT . Alpha-fetoprotein-derived antiestrotrophic octapeptide . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1501 . 1 . 33–43 . April 2000 . 10727847 . 10.1016/S0925-4439(00)00008-9 .
  2. Andersen TT, Georgekutty J, Defreest LA, Amaratunga G, Narendran A, Lemanski N, Jacobson HI, Bennett JA . An alpha-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen . British Journal of Cancer . 97 . 3 . 327–33 . August 2007 . 17637684 . 10.1038/sj.bjc.6603882 . 2360332 .
  3. Jacobson HI, Thompson WD, Janerich DT . Multiple births and maternal risk of breast cancer . American Journal of Epidemiology . 129 . 5 . 865–73 . May 1989 . 2641667 . 10.1093/oxfordjournals.aje.a115220.
  4. Crandall BF . Alpha-fetoprotein: a review . Critical Reviews in Clinical Laboratory Sciences . 15 . 2 . 127–85 . 1981 . 6169490 . 10.3109/10408368109105870. Lau . H. Lonin .
  5. Richardson BE, Hulka BS, Peck JL, Hughes CL, van den Berg BJ, Christianson RE, Calvin JA . Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancer risk . American Journal of Epidemiology . 148 . 8 . 719–27 . October 1998 . 9786226 . 10.1093/oxfordjournals.aje.a009691. free .
  6. Sonnenschein C, Ucci AA, Soto AM . Growth inhibition of estrogen-sensitive rat mammary tumors. Effect of an alpha-fetoprotein-secreting hepatoma . Journal of the National Cancer Institute . 64 . 5 . 1147–52 . May 1980 . 6154169 . 10.1093/jnci/64.5.1147 .
  7. Bennett JA, Zhu S, Pagano-Mirarchi A, Kellom TA, Jacobson HI . Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts . Clinical Cancer Research . 4 . 11 . 2877–84 . November 1998 . 9829755 .
  8. DeFreest LA, Mesfin FB, Joseph L, McLeod DJ, Stallmer A, Reddy S, Balulad SS, Jacobson HI, Andersen TT, Bennett JA . Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization . The Journal of Peptide Research . 63 . 5 . 409–19 . May 2004 . 15140158 . 10.1111/j.1399-3011.2004.00139.x .
  9. Parikh RR, Gildener-Leapman N, Narendran A, Lin HY, Lemanski N, Bennett JA, Jacobson HI, Andersen TT . Prevention of N-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP . Clinical Cancer Research . 11 . 23 . 8512–20 . December 2005 . 16322315 . 10.1158/1078-0432.CCR-05-1651 . free .
  10. Bennett JA, DeFreest L, Anaka I, Saadati H, Balulad S, Jacobson HI, Andersen TT . AFPep: an anti-breast cancer peptide that is orally active . Breast Cancer Research and Treatment . 98 . 2 . 133–41 . July 2006 . 16538538 . 10.1007/s10549-005-9140-5 . 29371187 .
  11. Web site: Identification of Cellular Binding Sites for a Novel Human Anti-Breast Cancer Peptide . DeFreest L, Bennett J . 2004-05-01 . Storming Media . 2008-11-09.
  12. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N . Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study . Journal of the National Cancer Institute . 90 . 18 . 1371–88 . September 1998 . 9747868 . 10.1093/jnci/90.18.1371 . free .
  13. Assikis VJ, Jordan VC . Gynecologic effects of tamoxifen and the association with endometrial carcinoma . International Journal of Gynaecology and Obstetrics . 49 . 3 . 241–57 . June 1995 . 9764862 . 10.1016/0020-7292(95)02387-R . 25099453 .
  14. Kraft JK, Hughes T . Polypoid endometriosis and other benign gynaecological complications associated with Tamoxifen therapy-a case to illustrate features on magnetic resonance imaging . Clinical Radiology . 61 . 2 . 198–201 . February 2006 . 16439226 . 10.1016/j.crad.2005.09.007 .

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