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Annals of Oncology 15:151-160, 2004
© 2004 European Society for Medical Oncology

Original Paper

Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells

Received 7 March 2003; revised 18 June 2003; accepted 13 August 2003

Background:

To evaluate the impact of dihydrofolate reductase (DHFR) and reduced folate carrier (RFC) genes on methotrexate (MTX) resistance in osteosarcoma cells in relation to retinoblastoma (RB1) gene status.

Materials and methods:

A series of human osteosarcoma cell lines—either sensitive or resistant to MTX—and 16 osteosarcoma tumour samples were used in this study.

Results:

In U-2OS MTX-resistant variants, and in other RB1-positive cell lines, MTX resistance was associated with increased levels of DHFR and with a slight decrease of RFC gene expression. In Saos-2 MTX-resistant variants, and in another RB1-negative cell line, development of MTX resistance was associated with a decrease in expression of RFC, without any significant involvement of DHFR. In osteosarcoma clinical samples, amplification of the DHFR gene at clinical onset appeared to be more frequent in RB1-positive compared with RB1-negative tumours.

Conclusions:

Amplification of the DHFR gene may occur more frequently in the presence of RB1-mediated negative regulation of its activity and can be present at clinical onset in osteosarcoma patients. Simultaneous evaluation of RFC, DHFR and RB1 gene status at the time of diagnosis may become the basis for the identification of potentially MTX-unresponsive osteosarcoma patients, who could benefit from treatment protocols with alternative antifolate drugs.

M. Serra1,*, G. Reverter-Branchat1, D. Maurici1,2, S. Benini1, J.-N. Shen1, T. Chano1, C.-M. Hattinger1, M.-C. Manara1, M. Pasello1, K. Scotlandi1 and P. Picci1

1 Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna; 2 European Centre for the Validation of Alternative Methods (ECVAM), Institute for Health and Consumer Protection (IHCP), Ispra, Italy

Key words: dihydrofolate reductase, drug resistance, methotrexate, osteosarcoma, reduced folate carrier, retinoblastoma gene


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