Ewing sarkomunda P-glikoprotein ekspresyonunun prognostik anlamı

Giriş: Ewing sarkomu primer malign kemik tümörlerinin %6–9’unu oluşturur. Modern kemoterapi protokollerinin uygulanmadığı dönemlerde, Ewing sarkomu hastalarının yaşam süreleri hemen hemen aynıydı. Günümüzde, çoklu kemoterapinin kullanıldığı protokoller sayesinde yaşam süresi uzamıştır. Ancak bazı hastalarda kemoterapiye yanıt çok iyi olurken, bazılarında yetersiz kalmaktadır. Bu, tümör hücrelerinin çoklu sitotoksik ilaçlara direnci (MDR) ile ilişkilendirilebilir. Sitoplazmik membranda lokalize olan P-glikoprotein (PGP) ilaçların hücre dışına atım mekanizmala-rını regüle eder. Ewing sarkomunda sıklıkla kullanılan tedavi protokolü, Vinkristin, Aktinomisin-D, Siklofosfamid ve Adriamisini içerir. Bunlardan siklofosfamid hariç diğer tüm ajanlar PGP’nin sübstratıdır. Dolayısı ile PGP pozitifliğini gösterebildiğimiz tümör olgularının, bu üç ajana dirençli olması beklenir. Gereç ve Yöntem: Çalışmamızda, 1986 ile 1999 yılları Ewing sarkomu tanı almış POG#8850 (VAC+Adr) kemote-rapi protokolü ile tedavi edilmiş 36 olgu “Ewing sarkomu PGP prognostik grubuna” alındı. Otuz altı olguya, PGP’nin eksternal epitopunu tanıyan C494 monoklonal antikoru uygulandı. Bulgular: PGP, 16 olguda negatif, 5 olguda fokal pozitif, 15 olguda da diffüz pozitif olarak izlendi. PGP negatif grup ile PGP diffüz pozitif grup arasında istatistiksel olarak anlamlı farklılık bulundu (p0,05). PGP pozitif grup ile nega-tif grubun yaşam süreleri arasındaki fark istatistiksel olarak anlamlıydı (p

Prognostic importance of P-glicoprotein expression in ewing sarcoma

Introduction: Ewing sarcoma is responsible from 6–9% of the primary malignant bone tumors. Before the mo-dern chemotherapy era, survival time of these patients were the same as other tumor cases. Nowadays, by using multiple chemotherapy regimens, survival time is much longer than before. However, some patients respond to chemotherapy very well while some others don’t. This may be related to multiple drug resistance (MDR) of the tumor cells. Located on the cytoplasmic membrane, P-glicoprotein (PGP) regulates the excretion mechanisms of the drugs outside the cell. Treatment protocol of Ewing sarcoma usually consists Vincristin, Actinomycin-D, Cyclophosphamide and Adriamicin. Except Cyclophosphamide, all the other drugs are the substrates of PGP. So, in tumors in which we can show the PGP positivity, we can assume that they are resistant to the so-called drugs. Materials and methods: In our study conducted between the years 1986–1999, 36 cases of Ewing sarcoma treated with POG#8850 (VAC+Adr) chemotherapy protocol were included in “Ewing sarcoma PGP prognostic group”. C494 monoclonal antibody which recognizes the external epitope of PGP was administered to all patients. Results: PGP was found focally positive in 5 and diffusely positive in 15 of the cases. Sixteen cases were negative for PGP. There was significant difference in survival times between diffusely positive PGP cases and the negative ones. There was no significant difference between focally positive PGP group and the others. Discussion: The results of this study indicate that PGP positivity in tumor cells can limit the efficacy of chemotherapy in Ewing sarcoma cases. We think that demonstration of PGP values in the first biopsy may help us in choosing the most appropriate chemotherapeutic agents.

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  • 1. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921;21:17-24
  • 2. Robert E. Fechner M.D, Stacey E. Mills, M.D. Armed Forces Institute of Pathology. Tumors of the bones and joints. 1993
  • 3. K. Krishnan Unni. Dahlin’s Bone Tumors; General Aspects and data on 11087 Cases. Lippincott-Raven Philadelphia 1996
  • 4. Dahlin DC, Coventy MD, Scanlon PW. Ewing's sarcoma: a critical analysis of 165 cases. J Bone Joint Surg Am 1962;43:185.
  • 5. Picci P, Rougraff BT, Bacci G.Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing sarcoma of extremities.J Clin oncol 1993
  • 6. Bacci G,Picci P, Ruggeri P.No advantages in addition of ifosfamide and VP-16 to the standard four –drug regimen in the maintenance Phase of neoadjuvantt chemotherapy of Ewing’s sarcoma of bone; results of two sequential studies. J Chemother 1993
  • 7. Helen S.L Chan, Paul S. Thorner, George Haddad and Victor Ling :Immunohistochemical Detection of P-Glycoprotein: Prognostic Correlation in Soft Tissue Sarcoma of Childhood. J.Clin Oncol 1990; 8: 689-704
  • 8. Vergier B, Cany L, Bonnet F, Robert J, et al. Expression of MDRI/P-glycoprotein in human sarcomas. BR J Cancer 1993; 68:1221-1226.
  • 9. Hyde SC, Emsley P, Hartshorn MJ, et al. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance, and bacterial transport. Nature 1990, 346, 362-365.
  • 10. Mimura CS, Holbrook SR, Ames GF-L. Structural model of the nucleotide-binding conserved component of periplasmic permeases. Proc Natl Acad Sci USA 1991, 88, 84-88.
  • 11. U.A. Germann. P-Glycoprotein a madiator of multidrug resistance in tumour cells. European Journal of Cancer 1996, vol 32A, no.6, 927-944
  • 12. Vergier B et al. Expression of MDR1/P-gp in human sarcomas. Br J Cancer 1993
  • 13. Hijazi YM et al. Immunohistochemical detection of P-gp in Ewing’s sarcoma and peripheral primitive neuroectodermal tumors before and after chemotheraphy. Am J Clin Pathol 1994
  • 14. Chan HS, Grogan TM, DeBoer G, Haddad G, Ling V. Diagnosis and Reversal of Multidrug Resisitance in Paediatric Cancer. European Journal of Cancer 1996, vol 32A, no.6, 1051-1061
  • 15. Triche TJ. Multiple-drug Resistance in Ewing’s sarcoma and PNET. American Journal of Clinical Pathology, 1994 july 1-2, editorial
  • 16. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Ann Rev Biochem 1989, 58, 137-171
  • 17. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Ann Rev Biochem 1993, 62,385-427.
  • 18. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, et al. Cellular localization of the multidrug resist¬ance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987, 84, 7735-7738
  • 19. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein, P170: evidence for localization in brain capillaries and cross- reactivity of one antibody with a muscle protein. J Histochem Cytochem 1989, 37, 159-164
  • 20. Cordon-Cardo C, O'Brian JP, Casals D, et al. Multidrug resist¬ance gene (P-glycoprotein) is expressed by endothelial cells at the blood-brain barrier sites. Proc Natl Acad Sci USA 1989, 86, 695-698
  • 21. Arceci RJ, Croop JM, Horwitz SB, Housman DE. The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci USA 1988, 85, 4350-1354
  • 22. Chambers TC. Phosphorylation of proteins involved in multidrug resisance. In Gupta S, Tsuruo T, ed. Multidrug Resistance in Cancer Cells. Chichester, U.K., John Wiley & Sons, 1996
  • 23. Lankelma J, Spoelstra EC, Dekker H, Broxterman HJ. Evidence for daunomycin efflux from multidrug-resistant 2780AD human ovarian carcinoma cells against a concentration gradient. Biochim Biophys Acta 1990, 1055, 217-222.
  • 24. Ruetz S, Gros P. Functional expression of P-glycoprotein in secretory vesicles. J Biol Chem 1994,269, 12277-12284
  • 25. Pastan I., Gottesman M. Multiple-Drug Resistance in Human Cancer. N. EngI J. Med 1987; 316, 1388-93
  • 26. Slater L, Sweet P, Wetzel M, Stupecky M, Osann K. Comparison of cyclosporin A, verapamil, PSC-833 and cremophor EL as enhancing agents of VP-16 in murine lymphoid leukemias. Lenkemia Res 1995, 19, 543-548
  • 27. Miller TP, Grogan TM, Dalton WS, Spier CM, Scheper RJ, Salmon SE. Pgp expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 1991,9, 17-24
  • 28. Sonneveld P, Durie BG, Lokhorst HM, et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leu¬kaemia Group of the EORTC and the HOVON. The Lancet 1992,340,255 259
  • 29. Cowie FJ, Pinkerton CR, Phillips M, et al. Continuous-infusion verapamil with etoposide in relapsed or resistant paediatric cancers. Br J Cancer 1995, 71, 877- 881
  • 30. Takeshita H, Gebhardt MC, Springfield DS, Kusuzaki K, Mankin HJ. Experimental models for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines. J Bone Joint Surg Am 1996 Mar;78(3):366-75
  • 31. Lacueva FJ, Teruel A, Calpena R, Medrano J, et al. Detection of P-glycoprotein in frozen and paraffin-embedded gastric adenocarcinoma tissues using a panel of monoclonal antibodies. Histopathology 1998 Apr;32(4):328-34
  • 32. Chan HSL, Thorner PS, Haddad G, Ling V. Immunohistochemical detection of P-gp: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol 1990,8,689-704
  • 33. Roessner A.et al. Prognostic implication of immunodetection of P-gp in Ewing’s sarcoma. Cancer Res Clin Oncol 1993
  • 34. Perri T, Fogel M, Mor S, Horev G, et al. Effect of P-glycoprotein expression on outcome in the Ewing family of tumors. Pediatr Hematol Oncol 2001 Jul-Aug;18(5):325-34