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KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ

Year 2015, Volume: 19 Issue: 3, 290 - 297, 04.07.2015

Özge Özcan Miriş Dikmen

https://doi.org/10.12991/mpj.201519394607

Abstract

mTOR (Mammalian Target of Rapamycin), fosfotidilinositid 3-kinaz (PI3K) ilişkili protein kinaz ailesine ait bir serin/treonin kinazdır. mTOR başta hücre büyümesi, metabolizması ve proliferasyonu dâhil olmak üzere bir dizi hücresel fonksiyonun düzenlenmesinde ve hücresel homeostazinin sağlanmasında önemli bir rol oynamaktadır.Kanserde önemli olduğu saptanan temel sinyalizasyon yollarından biri de (PI3K)/AKT kinaz kaskadıdır. Bu yolağın sıklıkla kanserde işleyişi bozulur ve bu yüzden de mTOR önemli bir antitümör hedef olmuştur. Antikanser ajanlar olarak mTOR inhibitörleri, rapamisin ve ondan türetilmiş temsirolimus, everolimus ve deforolimus (ridaforolimus)’tan oluşturmaktadır. Rapamisin ve analogları hem in vitro hem de in vivo kanser hücrelerinin proliferasyonunu inhibe etmektedir. Bu nedenle mTOR inhibitörleri birçok kanser tipi için önemli bir hedeftir.

Keywords

mTOR inhibitörleri PI3K/AKT kanser rapamisin

References

  • Doğan AL, Güç D. Sinyal iletimi mekanizmaları ve kanser. Hacettepe Tıp Dergisi 2004;35: 34-42.
  • Demirkazık A, Özal G. Prostat kanserinde hedefe yönelik tedavinin yeri. Üroonkoloji Bülteni 2010; 2: 64-68.
  • Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev 2006; 5; 671- 678.
  • Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001;411:355-364.
  • Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9(8): 550-562.
  • Wang Y, Mikhailova M, Bose S, Pan CX, deVere White RW, Ghosh PM. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 2008;27(56):7106-7117.
  • Kırkalı Z, Tüzel E. İleri evre böbrek hücreli kanser tedavisinde yeni gelişmeler. Türk Üroloji Dergisi 2007; 33(4): 385-391.
  • Laplante M, Sabatini DM. mTOR signaling at a glance. Journal of Cell Science 2009;122(20): 3589-3592.
  • Wysocki PJ. mTOR in renal cell cancer: modulator of tu¬mor biology and therapeutic target. Expert Rev Mol Diagn, 2009;9:231-241.
  • -
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501.
  • Bellacosa A, Chan TO, Ahmed NN et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 1998; 17: 313-325.
  • Shaw RJ, Cantley LC. Ras, PI(3)K, and mTOR signalling controls tumor cell growth. Nature 2006; 441: 424-430.
  • Pawson T. Introduction: Protein kinases. FASEB J 1994; 8:1112-1113.
  • Tığlı, H., (2009), Hücre Büyümesi İle İlgili mTOR Sinyal Yolağında Yer Alan Rheb Proteininin Mesane Kanserli Hastalarda Araştırılması, Doktora Tezi, İstanbul Üniversitesi, Sağlık Bilimleri Enstitüsü Tıbbi Biyoloji Anabilim Dalı, İstanbul.
  • Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-183.
  • Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25: 903-915.
  • Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
  • Figlin RA, Brown E, Armstrong AJ et al. NCCN task force report: mTOR inhibition in solid tumors. JNCCN 2008; 6: 1-20.
  • Toschi A, Lee E, Gadir N, Ohh M, Foster DA. Differen¬tial dependence of hypoxia- inducible factors 1a and 2a on mTORC1 and mTORC2. J Biol Chem 2008;283:34495-34499.
  • Hara K, Maruki Y, Long X, Yoshino K, Oshiro N et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110: 177-189.
  • Sabatini DM, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101
  • Zhou H, Huang S. mTOR signaling in cancer cell motility and tumor metastasis. Crit Rev Eukaryot Gene Expr 2010; 20: 1-16.
  • Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regu¬lation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci 2005;102: 8204-8209.
  • Thomas G, Hall MN. TOR signaling and control of control of cell growth. Curr Opi Cell Biol 1997; 9:782-787.
  • Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-252.
  • Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermantation, isolation and charecterization. J. Antibiotic 1975; 28: 727-732.
  • Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18;1926-1935.
  • Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22: 909–918.
  • Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372; 449-456.
  • Agulnik M. New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma. cancer 2012;118(6): 1486–1497.
  • Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumori¬genesis: development and use of mTOR inhibitors in cancer therapy. J Hematol & Oncol 2009; 2: 1-12.
  • Vezina C, Kuldelski A, Sehgal SN. Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of producing streptomycete and isolation of the active principle. J Antibiot 1975; 28: 721-726.
  • RxMediaPharma, Ed: Üstüneş L, 2014.
  • Kahan BD, Julian BA, Pescovitz MD et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase 2 trial rapamune study group. Transplantation1999; 68: 1526-1532.
  • Demirci C, Töz H. Renal transplantasyonda mTOR inhibitörleri ve mikofenolat mofetilin kombine kullanımı. Türk Nefroloji Diyaliz ve Transplantasyon Dergisi 2008;17:33-38.
  • Stegall MD, Larson TS, Prieto M et al. Kidney transplantation without calcineurin inhibitors using sirolimus. Transplantat Proc 2003:35;125S-127S.
  • Atalay C, Yılmaz KB, Karaman N, Altınok M. Klasik Kaposi sarkomunda tedavi. Erciyes Tıp Dergisi 2007; 29(2):128-131.
  • Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: An overview. Cancer Treatment Reviews 2009;35: 148–159.
  • Frost P, Moatamed F, Hoang B et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cellsin a xenograft model. Blood 2004;104(13):4181-4187.
  • Hudes G, Carducci M, Tomczak P et al. Global ARCC Trial; Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 200; 356(22): 2271-2281.
  • Halbert RJ, Figlin RA, Atkins MB, Bernal M et al. Treatment of patients with metastatic renal cell cancer. Cancer 2006; 107(10): 2375-2383.
  • Robins HI, Wen PY, Chang SM, Kuhn J, Lamborn K, Cloughesy T et al. Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas. ASCO Meeting Abstracts 2007;25 (Suppl. 18).
  • Eisen HJ, Tuzcu EM, Dorent R et al. Everolimus for the prevention of allograft rejection and vascolopathy in cardiac-transplant recipients, for the RAD B253 Study Group. N Engl J Med 2003;349: 847-858.
  • Yao JC, Phan AT, Chang DZ et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to inter¬mediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26: 4311-4318.
  • http://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus
  • European Medicines Agency. EMEA. http://www.ema.europa.eu/ema/index. 2014.
  • Cantor ME. First Quarter 2009 Development Progress and Financial Results. ARIAD raporu, No: 617-621-2208, USA, 2009.
  • Yüksel H, Demircan Sezer S, Küçük M, Çulhacı N, Erkuş M. İleri evre uterin karsinosarkomda uzun süreli hastalıksız sağkalım. Türk Jinekolojik Onkoloji 2012;66-68.
  • Sezak M, Öztop F. Ewing sarkomunda prognoz klinik ve histolojik bulgular ile belirlenebilir mi?. Ege Tıp Dergisi 2008; 47(2): 127-134.
  • Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008; 26: 361–367.

Year 2015, Volume: 19 Issue: 3, 290 - 297, 04.07.2015

Özge Özcan Miriş Dikmen

https://doi.org/10.12991/mpj.201519394607

Abstract

References

  • Doğan AL, Güç D. Sinyal iletimi mekanizmaları ve kanser. Hacettepe Tıp Dergisi 2004;35: 34-42.
  • Demirkazık A, Özal G. Prostat kanserinde hedefe yönelik tedavinin yeri. Üroonkoloji Bülteni 2010; 2: 64-68.
  • Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev 2006; 5; 671- 678.
  • Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001;411:355-364.
  • Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9(8): 550-562.
  • Wang Y, Mikhailova M, Bose S, Pan CX, deVere White RW, Ghosh PM. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 2008;27(56):7106-7117.
  • Kırkalı Z, Tüzel E. İleri evre böbrek hücreli kanser tedavisinde yeni gelişmeler. Türk Üroloji Dergisi 2007; 33(4): 385-391.
  • Laplante M, Sabatini DM. mTOR signaling at a glance. Journal of Cell Science 2009;122(20): 3589-3592.
  • Wysocki PJ. mTOR in renal cell cancer: modulator of tu¬mor biology and therapeutic target. Expert Rev Mol Diagn, 2009;9:231-241.
  • -
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489-501.
  • Bellacosa A, Chan TO, Ahmed NN et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 1998; 17: 313-325.
  • Shaw RJ, Cantley LC. Ras, PI(3)K, and mTOR signalling controls tumor cell growth. Nature 2006; 441: 424-430.
  • Pawson T. Introduction: Protein kinases. FASEB J 1994; 8:1112-1113.
  • Tığlı, H., (2009), Hücre Büyümesi İle İlgili mTOR Sinyal Yolağında Yer Alan Rheb Proteininin Mesane Kanserli Hastalarda Araştırılması, Doktora Tezi, İstanbul Üniversitesi, Sağlık Bilimleri Enstitüsü Tıbbi Biyoloji Anabilim Dalı, İstanbul.
  • Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-183.
  • Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25: 903-915.
  • Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
  • Figlin RA, Brown E, Armstrong AJ et al. NCCN task force report: mTOR inhibition in solid tumors. JNCCN 2008; 6: 1-20.
  • Toschi A, Lee E, Gadir N, Ohh M, Foster DA. Differen¬tial dependence of hypoxia- inducible factors 1a and 2a on mTORC1 and mTORC2. J Biol Chem 2008;283:34495-34499.
  • Hara K, Maruki Y, Long X, Yoshino K, Oshiro N et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110: 177-189.
  • Sabatini DM, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101
  • Zhou H, Huang S. mTOR signaling in cancer cell motility and tumor metastasis. Crit Rev Eukaryot Gene Expr 2010; 20: 1-16.
  • Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regu¬lation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci 2005;102: 8204-8209.
  • Thomas G, Hall MN. TOR signaling and control of control of cell growth. Curr Opi Cell Biol 1997; 9:782-787.
  • Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-252.
  • Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermantation, isolation and charecterization. J. Antibiotic 1975; 28: 727-732.
  • Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18;1926-1935.
  • Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22: 909–918.
  • Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372; 449-456.
  • Agulnik M. New developments in mammalian target of rapamycin inhibitors for the treatment of sarcoma. cancer 2012;118(6): 1486–1497.
  • Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumori¬genesis: development and use of mTOR inhibitors in cancer therapy. J Hematol & Oncol 2009; 2: 1-12.
  • Vezina C, Kuldelski A, Sehgal SN. Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of producing streptomycete and isolation of the active principle. J Antibiot 1975; 28: 721-726.
  • RxMediaPharma, Ed: Üstüneş L, 2014.
  • Kahan BD, Julian BA, Pescovitz MD et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase 2 trial rapamune study group. Transplantation1999; 68: 1526-1532.
  • Demirci C, Töz H. Renal transplantasyonda mTOR inhibitörleri ve mikofenolat mofetilin kombine kullanımı. Türk Nefroloji Diyaliz ve Transplantasyon Dergisi 2008;17:33-38.
  • Stegall MD, Larson TS, Prieto M et al. Kidney transplantation without calcineurin inhibitors using sirolimus. Transplantat Proc 2003:35;125S-127S.
  • Atalay C, Yılmaz KB, Karaman N, Altınok M. Klasik Kaposi sarkomunda tedavi. Erciyes Tıp Dergisi 2007; 29(2):128-131.
  • Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: An overview. Cancer Treatment Reviews 2009;35: 148–159.
  • Frost P, Moatamed F, Hoang B et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cellsin a xenograft model. Blood 2004;104(13):4181-4187.
  • Hudes G, Carducci M, Tomczak P et al. Global ARCC Trial; Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 200; 356(22): 2271-2281.
  • Halbert RJ, Figlin RA, Atkins MB, Bernal M et al. Treatment of patients with metastatic renal cell cancer. Cancer 2006; 107(10): 2375-2383.
  • Robins HI, Wen PY, Chang SM, Kuhn J, Lamborn K, Cloughesy T et al. Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas. ASCO Meeting Abstracts 2007;25 (Suppl. 18).
  • Eisen HJ, Tuzcu EM, Dorent R et al. Everolimus for the prevention of allograft rejection and vascolopathy in cardiac-transplant recipients, for the RAD B253 Study Group. N Engl J Med 2003;349: 847-858.
  • Yao JC, Phan AT, Chang DZ et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to inter¬mediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26: 4311-4318.
  • http://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus
  • European Medicines Agency. EMEA. http://www.ema.europa.eu/ema/index. 2014.
  • Cantor ME. First Quarter 2009 Development Progress and Financial Results. ARIAD raporu, No: 617-621-2208, USA, 2009.
  • Yüksel H, Demircan Sezer S, Küçük M, Çulhacı N, Erkuş M. İleri evre uterin karsinosarkomda uzun süreli hastalıksız sağkalım. Türk Jinekolojik Onkoloji 2012;66-68.
  • Sezak M, Öztop F. Ewing sarkomunda prognoz klinik ve histolojik bulgular ile belirlenebilir mi?. Ege Tıp Dergisi 2008; 47(2): 127-134.
  • Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008; 26: 361–367.
There are 51 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Articles
Authors

Özge Özcan This is me

Miriş Dikmen

Publication Date July 4, 2015
Published in Issue Year 2015 Volume: 19 Issue: 3

Cite

APA Özcan, Ö., & Dikmen, M. (2015). KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ. Marmara Pharmaceutical Journal, 19(3), 290-297. https://doi.org/10.12991/mpj.201519394607
AMA Özcan Ö, Dikmen M. KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ. J Res Pharm. August 2015;19(3):290-297. doi:10.12991/mpj.201519394607
Chicago Özcan, Özge, and Miriş Dikmen. “KANSER TEDAVİSİNDE MTOR İNHİBİTÖRLERİ”. Marmara Pharmaceutical Journal 19, no. 3 (August 2015): 290-97. https://doi.org/10.12991/mpj.201519394607.
EndNote Özcan Ö, Dikmen M (August 1, 2015) KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ. Marmara Pharmaceutical Journal 19 3 290–297.
IEEE Ö. Özcan and M. Dikmen, “KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ”, J Res Pharm, vol. 19, no. 3, pp. 290–297, 2015, doi: 10.12991/mpj.201519394607.
ISNAD Özcan, Özge - Dikmen, Miriş. “KANSER TEDAVİSİNDE MTOR İNHİBİTÖRLERİ”. Marmara Pharmaceutical Journal 19/3 (August 2015), 290-297. https://doi.org/10.12991/mpj.201519394607.
JAMA Özcan Ö, Dikmen M. KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ. J Res Pharm. 2015;19:290–297.
MLA Özcan, Özge and Miriş Dikmen. “KANSER TEDAVİSİNDE MTOR İNHİBİTÖRLERİ”. Marmara Pharmaceutical Journal, vol. 19, no. 3, 2015, pp. 290-7, doi:10.12991/mpj.201519394607.
Vancouver Özcan Ö, Dikmen M. KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ. J Res Pharm. 2015;19(3):290-7.

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