title: Single agent and combination studies of pralatrexate and molecular correlates of sensitivity.
abstract: BACKGROUND
  Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents.
  
  
  METHODS
  Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay. Gene expression was evaluated using qRT-PCR.
  
  
  RESULTS
  Pralatrexate and methotrexate had a similar pattern of cytotoxicity, pralatrexate being more potent. Pralatrexate potentiated the effects of platinum drugs, antimetabolites and EGFR inhibitors. Dose- and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of FPGS. Acquired resistance to pralatrexate was associated with decreased RFC-1 expression, whereas methotrexate resistance correlated with increased DHFR expression, suggesting different mechanisms of acquired resistance.
  
  
  CONCLUSIONS
  Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome.
authors.affiliation: INSERM U728, RayLab, and Departments of Medical Oncology, Beaujon University Hospital, Assistance Publique - Hôpitaux de Paris, Paris 7 Diderot, 100 boulevard du Général Leclerc, Clichy 92110, France.
authors.forename: M
authors.initials: M
authors.lastname: Serova
authors.forename: I
authors.initials: I
authors.lastname: Bieche
authors.forename: M-P
authors.initials: MP
authors.lastname: Sablin
authors.forename: G J
authors.initials: GJ
authors.lastname: Pronk
authors.forename: M
authors.initials: M
authors.lastname: Vidaud
authors.forename: E
authors.initials: E
authors.lastname: Cvitkovic
authors.forename: S
authors.initials: S
authors.lastname: Faivre
authors.forename: E
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D000630:Aminopterin; D008727:Methotrexate