title: Impairments in antifolate transport are common in retinoblastoma tumor samples.
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.
  
  
  METHODS
  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 overexpression. 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.
  
  
  CONCLUSIONS
  These results would support consideration of a phase II study to determine the effectiveness of trimetrexate for recurrent intra-ocular retinoblastoma.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Gorlick
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: Beth Anne
authors.initials: BA
authors.lastname: Mazza
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Dunkel
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport / Q000235:genetics; D002648:Child; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005493:Folic Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000517:prevention & control; D058978:Reduced Folate Carrier Protein; D019572:Retinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D012175:Retinoblastoma / Q000378:metabolism* / Q000473:pathology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D016597:Trimetrexate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C036539:fluoresceinated methotrexate; D013762:Tetrahydrofolate Dehydrogenase; D016597:Trimetrexate; D008727:Methotrexate