Osteosarkomda MDR/P-gp fenotipinin diferansiyasyon ile ilişkisi

Bazı deneysel çalışmaların sonucunda, diğer malignitelerde savunulduğu gibi, osteosarkom da (OS) da, p-glikoprotein (P-gp) pozitifliğinin diferansiyasyonla doğru orantılı olarak arttığı iddia edilmektedir. Bu nedenle P-gp'nin kötü prognostik belirleyici olamayacağı öne sürülmektedir. Bu çalışmada OS'larda farklı diferansiyasyon gösteren alanlardaki P-gp pozitifliğinin dağılımı saptanarak diferansiyasyonla ilişkisi sorgulanmıştır. 1984-2000 yılları arasında, Anabilim Dalımızda osteosarkom tanısı almış, 81 primer ameliyat, 82 biyopsi, 13 akciğer, bir aksiller lenf nodülü, bir kosta metastazı, üç lokal rekürrens ameliyat materyalinden hazırlanan 337 kesite immunohistokimyasal yöntemle P-gp boyası uygulanmıştır. Kesitlerde saptanan toplam 544 değişik diferansiyasyon alanında P-gp boyanma özellikleri 0-6 arası skorlanmıştır. Çalışmamızda OS'larda P-gp varlığının matriks içeriği ve diferansiyasyon ile bir ilişkisi olmadığı saptanmıştır. OS'ların histolojik alt tipleri göz önüne alınarak yapılan analizlerde de boyanma oranının farklılık göstermediği bulunmuştur. Bu proteinin diferansiyasyon ile ilişkisi olabileceğini ön gören kaynaklarla uyuşmayan bir sonuç elde edilmiştir. P-gp boyanması diferansiyasyondan bağımsız bir belirleyici gibi görünmektedir.

The correlation of MDR/P-gp phenotype and differentiation of osteosarcoma

Recent experimental studies on osteosarcomas (OS) have postulated that similar to other malignancies, p-glycoprotein (P-gp) positivity is directly correlated with differentiation. Therefore, it has been hypothesized that P-gp cannot be a marker of poor prognosis. In this study, the distribution of P-gp positivity in different areas of OSs with variable differentiation pathways is assessed and its relationship with differentiation is questioned. The cases, which have received the diagnosis of OS in our department between 1984-2000, were included in the study. A total of 337 sections were immunohistochemically stained for P-gp, which consisted of 81 primary surgical materials, 82 biopsies, 13 lung specimens, one axillary lymph node and one rib metastasis, and three local recurrence materials. The P-gp staining patterns were scored between 0 and 6 on a total of 544 areas with different differentiation pathways. Our results have shown that P-gp expression of OSs has no correlation with the matrix content and differentiation. Furthermore, the analysis of the histological subtypes did not present any differences in the staining patterns. In conclusion, despite the previous reports demonstrating correlation of this protein with differentiation, It appears that P-gp staining of OSs is an independent factor.

___

  • 1. Bert L Lum and Michael P. Gosland. MDR ekspression in normal tissues. Drug resistance in clinical oncol. and hematol 1995 ; 9:319-335.
  • 2. Holzmayer TA, Hilsenbeck S, Von Hoff DD, Roninson IB. Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst 1992; 262:84-89.
  • 3. Keizer HG, Schuurhuis GJ, Broxterman HJ et al. Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells, Cancer Research 1989; 49:2988-2993.
  • 4. Kelley SL, Basu A, Teicher BA et al. Overxpression of metallothionein confers resistance to anticancer drugs. Science 1988; vol. 241:1813-1815.
  • 5. Kessel D, Bosmann HB. On the characteristics of actinomycin D resistance in L51784 cells. Cancer Res 1970; 30:2695-2701.
  • 6. Leighton JC and Goldstein LJ. P-gylcoprotein in adult solid tumors. Drug resistance in clinical oncol. and hematol 1995; Vol:9, 251-273.
  • 7. Mealey KL, Barhoumi R, Rogers K, Kochevar DT. Doxorubucin induced expression of P-glycoprotein in canine osteosarcoma celi line. Cancer Lett 1998; 126:187-192.
  • 8. Pastan I and Gottesman M. Multiple-drug resistance in human cancer. N. Engl. J. Med 1987; 316:1388-1393.
  • 9. Peltier Leonard F. Adbridged from Jaffe.N. Recent advances in the chemotherapy of metastatic osteogenic sarcoma (Cancer 1972; 30: 1627.). Clin. Ortopaedics and Related Research 1991; 270:5-7.
  • lO.Sutoh I, Kohno H, Nakashima Y et al. Concurrent expressions of metallothionein, glutathione S-transferse-pi, and Pglycoprotein in colorectal cancers. Dis. Colon Rectum 2000; 43: 221-232.
  • H.Takeshita H, Gebhard MC, Springfield DS et al. Experimental models for the study of drug resistance in osteosarcoma: Pglycoprotein- positive, murine osteosarcoma celi lines. J Bone Joint Surg Am 1996; 78:366-375.
  • 12. Samuels BL, Murray JL, Cohen MB et al. İncreased glutathione peroxidase activity in a human sarcoma celi line with inherent doxorubicin resistance. Cancer Research 1991; 51:512-527.
  • 13. Chan HS, Grogan TM, Haddad G et al. Standardizasyon of a single-cell assay for sensitive detection of multidrug resistance protein expression in normal and malignant cells in archival clinical samples. J Lab Clin Med 1997; 130:297-306.
  • 14. Oda Y, Dockhorn-Dvrorniczak B, Jurgens H, Roessner A. Expression of multidrug resistance-associated protein gene in ewing sarcoma and malignant peripheral neuroectodermal tumor of bone. J Cancer Res Clin Oncol 1997; 123:237-239.
  • 15. Scheffer GL, Wİnjgaard PLJ, Flens MJ et al. The drug resistance-related protein LRP is the majör vault protein. Nature (Med.) 1995; 1:578-582.
  • 16. Delamou A, Yamamoto T, Kato S, Kasai S. Histopathological assesment of multidrug resistance in gastric cancer: Expression of P-glycoprotein, multidrug resistance-associated protein, and lung resistance protein. Am J Surg 1999; 29:401-406.
  • 17. Filipits M, Suchomel RW, Dekan G et al. MRP and MDR1 gene expression in primary breast carcinomas. Clinical Cancer Research 1996; 2:1231-1237.
  • 18. Kusuzaki K, Takeshita H, Murata H et al. Relation between cellular doxorubucin binding ability to nuclear DNA and histologic response to preoperative chemotherapy in patients with osteosarcoma. Cancer 1998; 82:2343-2349.
  • 19.Linn SC, Pinedo HM, Van Ark-Otte J et al. Expression of drug resistance proteins in breast cancer, in relation to chemotherapy. Cancer 1997; 71:787-795.
  • 20. Oda Y, Schneider-Stock R, Rys J et al. Revers transcriptase-polimerase chain reaction amplification of MDR1 gene expression in adult soft tissue sarcomas. Diagn Mol Pathol 1996; 5:98-106.
  • 21. Maraldi NM, Zini N, Santi S et al. P-glycoprotein subcellüler localization and celi morphotype in MDR1 gene-transfected human osteosarcoma cells. Biol Celi 1999; 91:17-28.
  • 22. Maraldi NM, Zini N, Sabatelli P et al. Ultrastructural features and P-glycoprotein immunolocalization in Saos-2/DX 580 multidrug-resistant human osteosarcoma cells. J Submicrosc Cytol Pathol 1996; 28:93-100.
  • 23. Chen CJ, Chin JE, Ueda K et al. Internal duplication and homology with bacterial transport proteins in MDR-1 (P-glycoprotein) gene from multidrug-resistant human cells. Celi 1986; 47:371-380.
  • 24. Chin JE, Soffir R, Noonan KE et al. Structure and expression of the human MDR (P-glycoprotein) gene family. Molec, Celi, Biol 1989; 9:3808-3820.
  • 25. Mickley L and Fojo AT. Cancer-Clinical science in practice "Drug resistance in treatment of cancer". Cambridge University Press 1998:101-131.
  • 26. Fojo AT, Ueda K, Slamon DJ et al. Ekspression of a multidrug resistance gene in human tumors and tissues. Proc. Natl. Acad Sci USA 1987; 84:265-269.
  • 27. Fojo AT, Akiyama S, Gottesman MM et al. Reduced drug accumulation in multiple drug-resistance human KB carcinoma celi lines. Cancer Res 1985; 45:3002-3007.
  • 28. Levine EA., Holzmayer T, Bacus S et al. Evaluation of newer prognostic markers for adult soft tissue sarcomas. J Clin Oncol 1997; 15:3249-3257.
  • 29. Chan HSL, Thorner PS, Haddad G , Ling V. Immunohistochemical detection of p-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J. Clin Oncol 1990; 8:689-704.
  • 30. Jimenez RE, Zalupski MM, Frank JJ et al. Multidrug resistance phenotype in high grade soft tissue sarcoma (Correlation of Pglycoprotein immunohistochemistry with pathologic response to chemotherapy). Cancer 1999; 86:976-981.
  • 31. Jungsil R, Şahin Ayşegül, Jae YR et al. Immunohistochemical analysis of P-glycoprotein expression oorrelated with chemotherapy resistance in locally advanced breast cancer. Hum Pathol 1990; 21:787-791.
  • 32. Terek RM, Schwartz GK, Devaney K et al. Chemotherapy and P-glycoprotein expression in chondrosarcoma. J. Orthop Res 1998; 16:585-590.
  • 33. Eid H, Geczi L, Magori A et al. Drug resistance and sensitivity of germ celi testicular tumors: evaluation of clinical relevans of MDRI/Pgp, p53, and metallothionein (MT) proteins. Anticancer Res 1998; 18(4C):3059-3064.
  • 34. Weinstein RS, Jakate SM, Dominguez JM et al. Relationship of the expression of the multidrug resistance gene product (Pglycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Research 1991; 51:2720-2726.
  • 35. Chan HSL, Thorner PS, Haddad G, Ling V. immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol 1990; 8:689-704.
  • 36.Serra M, Scotlandi K, Manara MC et al. Evaluation of P-glycoprotein expression in soft tissue sarcomas of the extremities. Cytotechnology 1996; 19:253-256.
  • 37. Kuttesch JF, Parham DM, Luo X et al. P-glycoprotein expression at diagnosis may not be a primary mechanism of therapeutic failure in childhood rhabdomyosarcoma. J Clin Oncol 1996; 14:886-900.
  • 38. Lopes JM, Bruland OS, Bjerkehagen B et al. Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance. Pathol Res Pract 1997; 193:21-36.
  • 39. Baldini N, Scotlandi K, Barbanti-Brodano G et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N, Engl, J, Med 1995; 333:1380-1385.
  • 40. Baldini N, Scotlandi K, Serra M et al. P-glycoprotein expression in osteosarcoma: A basis for risk-adapted adjuvant chemotherapy. J Orthop Res 1999; 17: 629-632.
  • 41. Chan HSL, Grogan TM, Haddad G et al. P-glycoprotein expression: Critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer İnst 1997; 89: 1706-1715.
  • 42. Serra M, Scotlandi K, Manara MC et al. Analysis of P-glycoprotein expression in osteosarcoma. European Journal of Cancer 1995; 31 A: 1998-2002.
  • 43. Serra M, Maurici D, Scotlandi K et al. Relationship between P-glycoprotein expression and P53 status in high-grade osteosarcoma. İnt J Oncol 1999; 14:301-307.
  • 44. Chan HS, Grogan TM, DeBoer G et al. importance of P-glycoprotein as determinant of chemotherapy response in osteosarcoma. Proc Annu Meet Am Assoc Cancer Res 1996; 37 (A):2220-2225.
  • 45. Bodey B, Taylor CR, Siegel SE, Kaiser HE. immunocytochemical observation of multidrug resistance (MDR) p170 glycoprotein expression in human osteosarcoma cells: the clinical significance of MDR protein overexpression. Anticancer Research 1996; 15 (6B):2461-2468.
  • 46. Lee PD, Noble-Topham-SE, Bell RS, Andrulis İL. Quantitative analysis of multidrug resistance gene expression in human osteosarcomas. Br. J. Cancer 1996; 74:1046-1050.
  • 47. Posl M, Grahl K, Amling M et al. P-glycoprotein expression in osteosarcoma. Pathologe 1996; 17:50-55.
  • 48. Posl M, Amling M, Grahl K et al. P-glycoprotein expression in high grade central osteosarcoma and normal bone cells: An immunohistochemical study. Gen Diagn Pathol 1997; 142:317-325.
  • 49. Radig K, Haeckel C, Herting J et al. Expression of P-glycoprotein in high grade osteosarcomas with special emphasis on chondroblastic subtype. General & Diagnostic Pathology 1997; 142:139-145.
  • 50. Gorlick R, Huvos AG, Heller G et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 1999; 17:2781-2788.
  • 51.Kusuzaki K, Hirata M, Takeshita H et al. Relationship between P-glycoprotein positivity, doxorubicin binding ability and histologic response to chemotherapy in osteosarcomas. Cancer Lett 1999; 138:203-208.
  • 52. Dietel M. Polymerase chain reaction in diagnostic pathologie. Verh Dtsch Ges Pathol 1994; 78:136-145.
  • 53. Vergier B, Cany L, Bonnet F et al. Expression of MDR1/ P- glycoprotein in human sarcomas. Br J Cancer 1993; 68:1221- 1226.
  • 54. Kunikane H, Zalupski MM, Ramachandran C et al. Flow cytometric analysis of P-glycoprotein expression and drug efflux in human soft tissue and bone sarcomas. Cytometry 1997; 30:197-203.
  • 55. Scotlandi K, Serra M, Nicoletti G et al. Multidrug resistance and malignancy in human osteosarcoma. Cancer Research 1996; 56:2434-2439.
  • 56. Scotlandi K, Manara MC, Serra M et al. The Expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells. Oncogene 1999; 18:739-746.
  • 57. Takeshita H, Kusuzaki K, Ashihara T et al. Actin organization associated with the expression of multidrug resistant phenotype in osteosarcoma cells and the effect of actin depolymerization on drug resistance. Cancer Lett 1998; 126:75-81.
  • 58. Takeshita H, Kusuzaki K, Murata H et al. Osteoblastic differentiation and P-glycoprotein multidrug resistance in a murine osteosarcoma model. Br J Cancer 2000; 82:1327-1331.
  • 59. Park YB, Kim HS, Oh JH, Lee SH. The co-expression of p53 protein and P-glycoprotein is correlated to a poor prognosis in osteosarcoma. Int Orthop 2001; 24:307-310.
  • 60. Homicek FJ, Gebhardt MC, Wolfe MW et al. P-glycoprotein levels predict poor outcome in patients with osteosarcoma. Clin Orthop 2000; 373:11-17.
Ege Tıp Dergisi-Cover
  • ISSN: 1016-9113
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1962
  • Yayıncı: Ersin HACIOĞLU
Sayıdaki Diğer Makaleler

Pelvik operasyonlarda mesane ve üreter yaralanmaları

Hüseyin YILMAZ, SERVET ÖZDEN HACIVELİOĞLU, Ömer DİNÇER

Yetişkin Türk erkek ve kadınlarında OS parietale'nin kalınlık haritası morfometrik bir çalışma

HULKİ BAŞALOĞLU, MEHMET TURGUT, H. Kübra BAŞOĞLU

Mide adenokarsinomlarının lokalizasyonunda bir değişiklik var mı?

Rukiye VARDAR, Serhat BOR, Fulya GÜNŞAR, Murat Bülent ALKANAT, Ömer ÖZÜTEMİZ, Ahmet AYDIN, Müge TUNÇYÜREK, Ahmet MUSOĞLU, Tankut İLTER, Hanifi ÇAVUŞOĞLU

Asemptomatik neonatal kolelitiyazis: Olgu sunumu ve literatürün gözden geçirilmesi

Nurşen BELET, Ümit BELET, Gazi Ayhan KALAYCI, Şükrü KÜÇÜKÖDÜK

Prenatal diagnosis of trisomi 13: A case report

Rafael LEVI, Şaban ADAKAN, Mustafa Coşan TEREK, Murat ULUKUŞ, Mustafa ULUKUŞ, Erol TAVMERGEN

Overin primer rabdomyosarkomu: Olgu sunumu

Sevil SAYHAN, Osman ZEKİOĞLU, Yıldız ERHAN

Osteosarkomda MDR/P-gp fenotipinin diferansiyasyon ile ilişkisi

Gülçin BAŞDEMİR, Öz Özden ERSOY, Fikri ÖZTOP

Sağlığı geliştirici davranışların değerlendirilmesi amacıyla çok boyutlu sağlık anketi (ÇSA)'nin bausel ölçeği ile birlikte uygulanması

Özlen TURGUL, Fethi DOĞAN, Aliye MANDIRACIOĞLU, NİMET EMEL LÜLECİ

Fetal subraventricular tachycardia in one of the twin: A case report

Ertürk LEVENT, A. Ruhi ÖZYÜREK, Hasan GÜVEN, Aytül PARLAR

Deneysel karaciğer iskemi-reperfüzyon oluşturulan sıçanlarda E vitamini ve kafeik asit fenetil ester'in (CAPE) metabolik enzimlere etkileri

Efkan UZ, H. Ramazan YILMAZ, Mustafa IRAZ, Ersin FADILLIOĞLU, Hüseyin ÖZYURT, Sadık SÖGÜT, Ömer AKYOL