Impairments in antifolate transport are common in retinoblastoma tumor samples

Richard G. Gorlick, David H. Abramson, Rebecca Sowers, Beth Anne Mazza, Ira J. Dunkel

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background. Many patients with retinoblastoma have a genetic predisposition to cancer and external beam radiation therapy and alkylating agent chemotherapy may increase their risk of secondary malignancy. Identification of effective chemotherapy agents for retinoblastoma that are not associated with an elevated risk of secondary malignancy would be beneficial. Procedure. Twenty-six specimens of fresh retinoblastoma tumor cells were studied in vitro with a PT430 competitive displacement assay. Differential displacement of the PT430 by methotrexate and not trimetrexate was considered indicative of a defect in reduced folate carrier (RFC)-mediated transport. Elevations in the accumulation of PT430 were considered indicative of dihydrofolate reductase (DHFR) amplification. Results. In 9 of the 26 (35%) samples, displacement by methotrexate was less than half the displacement by trimetrexate indicative of a defect in the RFC. In 5 of the 26 (19%) samples, trimetrexate did not displace the PT430. In 7 of 26 (27%) samples, the peak PT430 accumulation was suggestive of DHFR over-expression. Overall 9 of 26 (35%) samples had no evidence of a transport defect or DHFR overexpression and would be anticipated to be potentially sensitive to methotrexate. In 15 of the 26 (58%), no defects existed in trimetrexate displacement or DHFR overexpression and would be anticipated to be potentially sensitive to trimetrexate. Conclusion. These results would support consideration of a phase II study to determine the effectiveness of trimetrexate for recurrent intra-ocular retinoblastoma.

Original languageEnglish (US)
Pages (from-to)573-576
Number of pages4
JournalPediatric Blood and Cancer
Volume50
Issue number3
DOIs
StatePublished - Mar 1 2008

Keywords

  • Chemotherapy
  • Developmental therapeutics
  • Drug resistance
  • Methotrexate
  • Retinoblastoma

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Gorlick, R. G., Abramson, D. H., Sowers, R., Mazza, B. A., & Dunkel, I. J. (2008). Impairments in antifolate transport are common in retinoblastoma tumor samples. Pediatric Blood and Cancer, 50(3), 573-576. https://doi.org/10.1002/pbc.21266