Mechanisms of methotrexate resistance in osteosarcoma

Wei Guo, John H. Healey, Paul A. Meyers, Marc Ladanyi, Andrew G. Huvos, Joseph R. Bertino, Richard Gorlick

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

High-dose methotrexate is a major component of current protocols for the treatment of osteosarcoma, but some tumors seem to be resistant. Potential mechanisms of resistance include decreased transport through the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR). To investigate methotrexate resistance, tumors were obtained from 42 patients with high-grade osteosarcoma. RFC and DHFR mRNA expression were studied by semiquantitative reverse transcription-PCR. The RFC and DHFR genes were studied for deletions and amplification by Southern blot. Thirteen of 20 (65%) osteosarcoma samples were found to have decreased RFC expression at the time of initial biopsy. At definitive surgery and relapse, 10 of 22 (45%) were found to have decreased RFC expression. Seventeen of 26 (65%) samples with a poor response to chemotherapy had decreased RFC expression, whereas 5 of 14 (36%) samples with a good response had a decrease (P = 0.03). None of the samples had an RFC gene deletion. Two of 20 samples (10%) showed increased DHFR expression at initial biopsy. The frequency of increased DHFR expression was significantly higher in metastatic or recurrent tumors (62%, P = 0.014). None of the samples showed evidence of DHFR gene amplification. The high frequency of decreased RFC expression in the biopsy material suggests that impaired transport of methotrexate is a common mechanism of intrinsic resistance in osteosarcoma. Increased DHFR expression in the pulmonary metastases may be a mechanism of acquired methotrexate resistance or a difference between primary and metastatic lesions.

Original languageEnglish (US)
Pages (from-to)621-627
Number of pages7
JournalClinical Cancer Research
Volume5
Issue number3
StatePublished - Mar 1999
Externally publishedYes

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Reduced Folate Carrier Protein
Tetrahydrofolate Dehydrogenase
Osteosarcoma
Methotrexate
Biopsy
Gene Amplification
Gene Deletion
Clinical Protocols
Southern Blotting
Reverse Transcription
Neoplasms
Neoplasm Metastasis
Recurrence
Drug Therapy
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Guo, W., Healey, J. H., Meyers, P. A., Ladanyi, M., Huvos, A. G., Bertino, J. R., & Gorlick, R. (1999). Mechanisms of methotrexate resistance in osteosarcoma. Clinical Cancer Research, 5(3), 621-627.

Mechanisms of methotrexate resistance in osteosarcoma. / Guo, Wei; Healey, John H.; Meyers, Paul A.; Ladanyi, Marc; Huvos, Andrew G.; Bertino, Joseph R.; Gorlick, Richard.

In: Clinical Cancer Research, Vol. 5, No. 3, 03.1999, p. 621-627.

Research output: Contribution to journalArticle

Guo, W, Healey, JH, Meyers, PA, Ladanyi, M, Huvos, AG, Bertino, JR & Gorlick, R 1999, 'Mechanisms of methotrexate resistance in osteosarcoma', Clinical Cancer Research, vol. 5, no. 3, pp. 621-627.
Guo W, Healey JH, Meyers PA, Ladanyi M, Huvos AG, Bertino JR et al. Mechanisms of methotrexate resistance in osteosarcoma. Clinical Cancer Research. 1999 Mar;5(3):621-627.
Guo, Wei ; Healey, John H. ; Meyers, Paul A. ; Ladanyi, Marc ; Huvos, Andrew G. ; Bertino, Joseph R. ; Gorlick, Richard. / Mechanisms of methotrexate resistance in osteosarcoma. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 3. pp. 621-627.
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