Prognostic significance of NF-κB in resectable gastric cancer treated with concomittant chemoradiotherapy

Yıl 2007, Cilt: 22 Sayı: 2, 69 - 73, 01.03.2007

Oğuz Galip Yıldız Serdar Soyuer İşın Soyuer Kadir Uçar Mete Gündoğ Bünyamin Kaplan Metin Özkan

Öz

OBJECTIVES The aim of this study is to determine the prognostic value of transcription factor nucleer factor kappa B ( N F -κB) in resectable gastric cancer patients treated with concurrent chemoradiotherapy. METHODS Forty-nine (35 males, 14 females; median age 55; range 2273 years) resectable gastric cancer patients treated with gastrectomy and adjuvant concurrent chemoradiotherapy were enrolled in this study. All patients received weekly 250 mg/ m2 5-FU chemotherapy and radiotherapy concomittantly after gastrectomy. Then patients received 4 cycles i.v bolus FUFA chemotherapy sequentialy as consolidation treatment 2-4 week after chemoradiotherapy. Immunohistochemistry staining was performed on paraffin embedded tissue. NF-κB monoclonal antibodies were used for the staining. RESULTS The progression free surv ival and overall surv ival dif er e nce were anal ised between NF-κB pos it ive and neg at ive groups. For NF-kB a specimen was judged posit ive if more than 10% of the total cancer cells in a single field of view showed a response. CONCLUSION In patients who NF-κB was stained more than 10%, the overall survival was worse and there was statistically significant difference between groups. But in two groups, no statistically significant difference due to disease free survival.

Anahtar Kelimeler

Gastrectomy, Chemotherapy, Adjuvant, Stomach Neoplasms, NF-kappa B, Survival Rate, Radiotherapy, Radiation Oncology

Gastrektomi sonrası adjuvan kemoradyoterapi uygulanan mide karsinomlu olgularda NF-kB'nin prognostik önemi

Öz

AMAÇ Gastrektomiden sonra adjuvan kemoradyoterapi uygulanan mide kanserli olgularda transkripsiyon faktör nükleer faktör kappa B'nin (NF-κB ) progresyonsuz sağkalım ve genel sağkalım yönünden prognostik önemi araştırıldı. GEREÇ VE YÖNTEM Çalışmaya evre II-IV mide karsinomlu gastrektomi ve adjuvan kemoradyoterapi ile tedavi edilen 49 olgu (35 erkek, 14 kadın; median yaş 55; dağılım 22-73) dahil edildi. Tüm olgulara gastrektomi sonrası adjuvan radyoterapi ile eş zamanlı haftada bir kez 250 mg/m2 dozunda haftalık i.v. bolus 5-FU verildi. Kemoradyoterapinin tamamlanmasından 2-4 hafta sonra konsolidasyon amaçlı ardışık dört kür Mayo Rejimi i.v. bolus tarzında uygulandı. Olgulara ait parafin bloklardan yeni kesitler alınarak NF-kB immünohistokimyasal boyası uygulandı. NF-kB için tümör dokusunda nükleer boyanmanın %10'dan az olan olgular negatif, %10'dan fazla olan olgular ise pozitif olarak değerlendirildi. BULGULAR Bu kritere göre yapılan değerlendirmede toplam 49 hastanın 29'unda (%59) NF-kB negatif, 20 hastada (%41) ise NF-kB pozitif boyandı. Gruplar arasında progresyonsuz sağkalım ve genel sağkalım açısından fark olup olmadığı araştırıldı. SONUÇ NF-kB pozitif (%10'dan fazla boyanan) grupta genel sağkalım istatistiksel olarak anlamlı ve daha kısa bulunmuşken, hastalıksız sağkalım yönünden iki grup arasında istatistiksel anlamlı fark gösterilemedi.

Anahtar Kelimeler

Kemoradyoterapi, mide kanseri/patoloji, immünohistokimya, NF-kappa B, prognostik faktör, sağkalım oranı

Kaynakça

• 1. Andela VB, Schwarz EM, Puzas JE, O’Keefe RJ, Rosier RN. Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res 2000;60(23):6557- 62.
• 2. Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997;17(1):3-9.
• 3. Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002;3(3):221-7.
• 4. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002;2(4):301-10.
• 5. Pahl HL. Activators and target genes of Rel/NFkappaB transcription factors. Oncogene 1999;18(49):6853-66.
• 6. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649-83.
• 7. Wang W, Abbruzzese JL, Evans DB, Chiao PJ. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 1999;18(32):4554-63.
• 8. Biswas DK, Dai SC, Cruz A, Weiser B, Graner E, Pardee AB. The nuclear factor kappa B (NF-kappa B): a potential therapeutic target for estrogen receptor negative breast cancers. Proc Natl Acad Sci U S A 2001;98(18):10386-91.
• 9. Lind DS, Hochwald SN, Malaty J, Rekkas S, Hebig P, Mishra G, et al. Nuclear factor-kappa B is upregulated in colorectal cancer. Surgery 2001;130(2):363-9.
• 10. Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS, et al. Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. Cancer 2000;89(11):2274-81.
• 11. Chen CD, Sawyers CL. NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Mol Cell Biol 2002;22(8):2862-70.
• 12. Yamanaka N, Sasaki N, Tasaki A, Nakashima H, Kubo M, Morisaki T, et al. Nuclear factor-kappaB p65 is a prognostic indicator in gastric carcinoma. Anticancer Res 2004;24(2C):1071-5.
• 13. Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, et al. Nuclear factorkappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 2001;7(12):4136-42.
• 14. Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR, et al. Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 2002;62(3):910-6.
• 15. Milligan SA, Nopajaroonsri C. Inhibition of NFkappa B with proteasome inhibitors enhances apoptosis in human lung adenocarcinoma cells in vitro. Anticancer Res 2001;21(1A):39-44.
• 16. Wang CY, Mayo MW, Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996;274(5288):784-7.
• 17. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 1996;274(5288):787-9.
• 18. Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, et al. Aberrant nuclear factorkappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest 1997;100(12):2952-60.
• 19. Shattuck-Brandt RL, Richmond A. Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. Cancer Res 1997;57(14):3032-9.
• 20.Jeremias I, Kupatt C, Baumann B, Herr I, Wirth T, Debatin KM. Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells. Blood 1998;91(12):4624-31.
• 21.Batra RK, Guttridge DC, Brenner DA, Dubinett SM, Baldwin AS, et al. IkappaBalpha gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them to tumor necrosis factor-alpha-mediated cell death. Am J Respir Cell Mol Biol 1999;21(2):238-45.
• 22. Pahl HL. Activators and target genes of Rel/NFkappaB transcription factors. Oncogene 1999;18(49):6853-66.
• 23. Prasad AV, Mohan N, Chandrasekar B, Meltz ML. Activation of nuclear factor kappa B in human lymphoblastoid cells by low-dose ionizing radiation. Radiat Res 1994;138(3):367-72.
• 24. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998;281(5381):1312-6.
• 25. Deveraux QL, Reed JC. IAP family proteins-suppressors of apoptosis. Genes Dev 1999;13(3):239-52.
• 26. Kim DW, Sovak MA, Zanieski G, Nonet G, RomieuMourez R, Lau AW, et al. Activation of NFkappaB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis 2000;21(5):871-9.
• 27. Wu JT, Kral JG. The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J Surg Res 2005;123(1):158-69.