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AFPep

January 01, 1970

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 edit

Background edit

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 edit

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 edit

AFPep inhibits estrogen-stimulated growth of immature mouse uterus and thus is antiestrogenic.[1] 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 edit

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.[2] 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 edit

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

References edit

  1. ^ a b Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT (April 2000). "Alpha-fetoprotein-derived antiestrotrophic octapeptide". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1501 (1): 33–43. doi:10.1016/S0925-4439(00)00008-9. PMID 10727847.
  2. ^ a b c Andersen TT, Georgekutty J, Defreest LA, Amaratunga G, Narendran A, Lemanski N, Jacobson HI, Bennett JA (August 2007). "An alpha-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen". British Journal of Cancer. 97 (3): 327–33. doi:10.1038/sj.bjc.6603882. PMC 2360332. PMID 17637684.
  3. ^ a b Jacobson HI, Thompson WD, Janerich DT (May 1989). "Multiple births and maternal risk of breast cancer". American Journal of Epidemiology. 129 (5): 865–73. doi:10.1093/oxfordjournals.aje.a115220. PMID 2641667.
  4. ^ Crandall BF; Lau, H. Lonin (1981). "Alpha-fetoprotein: a review". Critical Reviews in Clinical Laboratory Sciences. 15 (2): 127–85. doi:10.3109/10408368109105870. PMID 6169490.
  5. ^ Richardson BE, Hulka BS, Peck JL, Hughes CL, van den Berg BJ, Christianson RE, Calvin JA (October 1998). "Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancer risk". American Journal of Epidemiology. 148 (8): 719–27. doi:10.1093/oxfordjournals.aje.a009691. PMID 9786226.
  6. ^ Sonnenschein C, Ucci AA, Soto AM (May 1980). "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. doi:10.1093/jnci/64.5.1147. PMID 6154169.
  7. ^ Bennett JA, Zhu S, Pagano-Mirarchi A, Kellom TA, Jacobson HI (November 1998). "Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts". Clinical Cancer Research. 4 (11): 2877–84. PMID 9829755.
  8. ^ a b DeFreest LA, Mesfin FB, Joseph L, McLeod DJ, Stallmer A, Reddy S, Balulad SS, Jacobson HI, Andersen TT, Bennett JA (May 2004). "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. doi:10.1111/j.1399-3011.2004.00139.x. PMID 15140158.
  9. ^ Parikh RR, Gildener-Leapman N, Narendran A, Lin HY, Lemanski N, Bennett JA, Jacobson HI, Andersen TT (December 2005). "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. doi:10.1158/1078-0432.CCR-05-1651. PMID 16322315.
  10. ^ a b c Bennett JA, DeFreest L, Anaka I, Saadati H, Balulad S, Jacobson HI, Andersen TT (July 2006). "AFPep: an anti-breast cancer peptide that is orally active". Breast Cancer Research and Treatment. 98 (2): 133–41. doi:10.1007/s10549-005-9140-5. PMID 16538538. S2CID 29371187.
  11. ^ DeFreest L, Bennett J (2004-05-01). "Identification of Cellular Binding Sites for a Novel Human Anti-Breast Cancer Peptide". Storming Media. Retrieved 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 (September 1998). "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. doi:10.1093/jnci/90.18.1371. PMID 9747868.
  13. ^ Assikis VJ, Jordan VC (June 1995). "Gynecologic effects of tamoxifen and the association with endometrial carcinoma". International Journal of Gynaecology and Obstetrics. 49 (3): 241–57. doi:10.1016/0020-7292(95)02387-R. PMID 9764862. S2CID 25099453.
  14. ^ Kraft JK, Hughes T (February 2006). "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. doi:10.1016/j.crad.2005.09.007. PMID 16439226.

January 01, 1970
afpep, alpha, fetoprotein, peptide, orally, active, cyclic, amino, acid, peptide, with, molecular, weight, daltons, derived, from, anti, oncogenic, active, site, residues, alpha, fetoprotein, using, standard, amino, acid, abbreviations, sequence, cyclo, ektovn. 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 Contents 1 Biological activity 1 1 Background 1 2 Anti cancer effects 1 3 Mechanism of action 2 Combination therapy with tamoxifen 3 Route of administration 4 ReferencesBiological activity editBackground edit 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 edit 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 edit AFPep inhibits estrogen stimulated growth of immature mouse uterus and thus is antiestrogenic 1 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 editAFPep 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 2 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 editAFPep active whether administered intraperitoneally subcutaneously or orally 10 References edit a b Mesfin FB Bennett JA Jacobson HI Zhu S Andersen TT April 2000 Alpha fetoprotein derived antiestrotrophic octapeptide Biochimica et Biophysica Acta BBA Molecular Basis of Disease 1501 1 33 43 doi 10 1016 S0925 4439 00 00008 9 PMID 10727847 a b c Andersen TT Georgekutty J Defreest LA Amaratunga G Narendran A Lemanski N Jacobson HI Bennett JA August 2007 An alpha fetoprotein derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen British Journal of Cancer 97 3 327 33 doi 10 1038 sj bjc 6603882 PMC 2360332 PMID 17637684 a b Jacobson HI Thompson WD Janerich DT May 1989 Multiple births and maternal risk of breast cancer American Journal of Epidemiology 129 5 865 73 doi 10 1093 oxfordjournals aje a115220 PMID 2641667 Crandall BF Lau H Lonin 1981 Alpha fetoprotein a review Critical Reviews in Clinical Laboratory Sciences 15 2 127 85 doi 10 3109 10408368109105870 PMID 6169490 Richardson BE Hulka BS Peck JL Hughes CL van den Berg BJ Christianson RE Calvin JA October 1998 Levels of maternal serum alpha fetoprotein AFP in pregnant women and subsequent breast cancer risk American Journal of Epidemiology 148 8 719 27 doi 10 1093 oxfordjournals aje a009691 PMID 9786226 Sonnenschein C Ucci AA Soto AM May 1980 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 doi 10 1093 jnci 64 5 1147 PMID 6154169 Bennett JA Zhu S Pagano Mirarchi A Kellom TA Jacobson HI November 1998 Alpha fetoprotein derived from a human hepatoma prevents growth of estrogen dependent human breast cancer xenografts Clinical Cancer Research 4 11 2877 84 PMID 9829755 a b DeFreest LA Mesfin FB Joseph L McLeod DJ Stallmer A Reddy S Balulad SS Jacobson HI Andersen TT Bennett JA May 2004 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 doi 10 1111 j 1399 3011 2004 00139 x PMID 15140158 Parikh RR Gildener Leapman N Narendran A Lin HY Lemanski N Bennett JA Jacobson HI Andersen TT December 2005 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 doi 10 1158 1078 0432 CCR 05 1651 PMID 16322315 a b c Bennett JA DeFreest L Anaka I Saadati H Balulad S Jacobson HI Andersen TT July 2006 AFPep an anti breast cancer peptide that is orally active Breast Cancer Research and Treatment 98 2 133 41 doi 10 1007 s10549 005 9140 5 PMID 16538538 S2CID 29371187 DeFreest L Bennett J 2004 05 01 Identification of Cellular Binding Sites for a Novel Human Anti Breast Cancer Peptide Storming Media Retrieved 2008 11 09 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 September 1998 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 doi 10 1093 jnci 90 18 1371 PMID 9747868 Assikis VJ Jordan VC June 1995 Gynecologic effects of tamoxifen and the association with endometrial carcinoma International Journal of Gynaecology and Obstetrics 49 3 241 57 doi 10 1016 0020 7292 95 02387 R PMID 9764862 S2CID 25099453 Kraft JK Hughes T February 2006 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 doi 10 1016 j crad 2005 09 007 PMID 16439226 Retrieved from https en wikipedia org w index php title AFPep amp oldid 1186202344, wikipedia, wiki, book, books, library,

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