Abstract
Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still die due to their disease. Further improvements in the management of osteosarcoma may rely on a more individualised treatment strategy, as well as on the introduction of new drugs. To aid in the preclinical evaluation of new candidate substances against osteosarcoma, we have established 11 human osteosarcoma xenograft lines and characterised them with regard to response to five different reference drugs. Doxorubicin, cisplatin methotrexate, ifosfamide and lomustine were effective in 3/11, 3/11, 1/10, 5/11 and 4/11 of the xenografts, respectively. Five xenografts were resistant to all compounds tested. We also assessed the mRNA expression levels of the xenografts for the O6-Methylguanine DNA Methyltransferase (MGMT), DNA topoisomerase II-(Topo II)-α, Gluthathione-S-transferase (GST)-π, Multidrug-resistance related protein (MRP) 1 and Multidrug-resistance (MDR) 1 genes. There was an inverse correlation between the transcript levels of GST-π and doxorubicin growth inhibition (r= −0.66; p<0.05), and between the transcript levels of MGMT and the effect of lomustine (r= −0.72; p<0.01), whereas the expression of MRP1 and cisplatin growth inhibition was positively correlated (r=0.82; p<0.005. This panel of xenografts should constitute a good tool for pharmacological and molecular studies in osteosarcoma.
Similar content being viewed by others
References
Malawer MM, Link MP, Donaldson SS: Sarcomas of the Bone. In DeVita VT, Hellmann S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology 2001; 6th Edition (Volume 2):1891–1936.
Souhami R, Cannon S. Osteosarcoma. In Peckham M, Pinedo HM, Veronesi U, eds. Oxford Textbook of Oncology. Oxford, Oxford University Press 1995: 1969–1976.
Bruland OS, Pihl A. On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy. Eur J Cancer 33:1725–1731, 1997
Sambrook J, Fritsh EF, Maniatis T. Molecular Cloning: a Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbour Laboratory Press 1989; 2nd Edition.
Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13, 1983
Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci USA 81:1991–1995, 1984
Tsai-Pflugfelder M, Liu LF, Liu AA, et al: Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22. Proc Natl Acad Sci USA 85:7177–7181, 1988
Moscow JA, Townsend AJ, Goldsmith ME, et al: Isolation of the human anionic glutathione S-transferase cDNA and the relation of its gene expression to estrogen-receptor content in primary breast cancer. Proc Natl Acad Sci USA 85:6518–6522, 1988
Tano K, Shiota S, Collier J, et al: Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for 06-alkylguanine. Proc Natl Acad Sci USA 87:686–690, 1990
Zaman GJ, Flens MJ, van Leusden MR, et al: The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci USA 91:8822–8826, 1994
Fuqua SA, Fitzgerald SD, McGuire WL. A simple polymerase chain reaction method for detection and cloning of low-abundance transcripts. Biotechniques 9:206–211, 1990
Budach W, Budach V. Association of tumor growth on nude mice and poor clinical outcome in soft tissue sarcoma patients. J Cancer Res Clin Oncol 127:523–530, 2001
Hoffmann J, Schmidt-Peter P, Hansch W, et al: Anticancer drug sensitivity and expression of multidrug resistance markers in early passage human sarcomas. Clin Cancer Res 5:2198–204, 1999
Boven E, Pinedo HM, van Hattum AH, et al: Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. Br J Cancer 78:1586–1593, 1998
Budach W, Budach V, Stuschke M, et al: Efficacy of ifosfamide, dacarbazine, doxorubicin and cisplatin in human sarcoma xenografts. Br J Cancer 70:29–34, 1994
Meyer WH, Houghton JA, Houghton PJ, et al: Development and characterization of pediatrie osteosarcoma xenografts. Cancer Res 50:2781–2785, 1990
Harris MB, Cantor AB, Goorin AM, et al: Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study. Med Pediatr Oncol 24:87–92, 1995
Scotlandi K, Serra M, Nicoletti G, et al: Multidrug resistance and malignancy in human osteosarcoma. Cancer Res 56:2434–2439, 1996
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 18:739–746, 1999
Serra M, Scotlandi K, Reverter-Branchat G, et al: Value of Pglycoprotein and clinicopathologic factors as the basis for new treatment strategies in high-grade osteosarcoma of the extremities. J Clin Oncol 21:536–542, 2003
Serra M, Maurici D, Scotlandi K, et al: Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. Int J Oncol 14:301–307, 1999
Chan HS, Grogan TM, Haddad G, et al: P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer Inst 89:1706–1715, 1997
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 333:1380–1385, 1995
Post 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 142:317–325, 1997
Wunder JS, Bull SB, Aneliunas V, et al: MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol 18:2685–2694, 2000
Gorlick R, Huvos AG, Heller G, et al: Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 17:2781–2788, 1999
Suto R, Abe Y, Nakamura M, et al: Multidrug resistance mediated by overexpression of P-glycoprotein in human osteosarcoma in vivo. Int J Oncol 12:287–291, 1998
Radig K, Hackel C, Herting J, et al: Expression of P-glycoprotein in high grade osteosarcomas with special emphasis on chondroblastic subtype. Gen Diagn Pathol 142:139–145, 1997
Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92:1295–302, 2000
Ifergan I, Meller I, Issakov J, Assaraf YG. Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity. Cancer 98:1958–1966, 2003
Batist G, Tulpule A, Sinha BK, et al: Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J Biol Chem 261:15544–15549, 1986
Goto S, Ihara Y, Urata Y, et al. Doxorubicin-induced DNA intercalation and cavenging by nuclear glutathione S-transferase pi. Faseb J 15:2702–2714, 2001
Saburi Y, Nakagawa M, Ono M, et al. Increased expression of glutathione S-transferase gene in cis-diamminedichloroplatinum(II)-resistant variants of a Chinese hamster ovary cell line. Cancer Res 1989;49(24 Pt 1):7020–5.
Wang YY, Teicher BA, Shea TC, et al: Cross-resistance and glutathione-S-transferase-pi levels among four human melanoma cell lines selected for alkylating agent resistance. Cancer Res 49:6185–6192, 1989
Puchalski RB, Fahl WE. Expression of recombinant glutathione S-transferase pi, Ya, or Ybl confers resistance to alkylating agents. Proc Natl Acad Sci USA 87:2443–2447, 1990
Ban N, Takahashi Y, Takayama T, et al: Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide. Cancer Res 56:3577–3582, 1996
Gilbert L, Elwood LJ, Merino M, et al: A pilot study of pi-class glutathione S-transferase expression in breast cancer: correlation with estrogen receptor expression and prognosis in nodenegative breast cancer. J Clin Oncol 11:49–58, 1993
Shiga H, Heath El, Rasmussen AA, et al: Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. Clin Cancer Res 5:4097–4104, 1995
Green JA, Robertson LJ, Clark AH. Glutathione S-transferase expression in benign and malignant ovarian tumors. Br J Cancer 68:235–239, 1993
Bai F, Nakanishi Y, Kawasaki M, et al: Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with nonsmall cell lung carcinoma. Cancer 78:416–421, 1996
Uozaki H, Horiuchi H, Ishida T, et al: Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase pi, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Relationship with poor prognosis. Cancer 79:2336–2344, 1997
Kellner U, Sehested M, Jensen PB, et al: Culprit and victim — DNA topoisomerase II. Lancet Oncol 3:235–243, 2002
Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388–2399, 2002
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bruheim, S., Bruland, O.S., Breistol, K. et al. Human osteosarcoma xenografts and their sensitivity to chemotherapy. Pathol. Oncol. Res. 10, 133–141 (2004). https://doi.org/10.1007/BF03033741
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03033741