title: Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma.
abstract: BACKGROUND
  Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment.
  
  
  METHODS
  Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score.
  
  
  RESULTS
  qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients.
  
  
  CONCLUSIONS
  Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment.
authors: Department of Pathology and Neuropathology, University Hospital Essen, University of Duisberg-Essen, Essen, Germany. fabian.mairinger@uk-essen.de
authors: Fabian
authors: F
authors: Mairinger
authors: Claudia
authors: C
authors: Vollbrecht
authors: Iris
authors: I
authors: Halbwedl
authors: Martina
authors: M
authors: Hatz
authors: Elvira
authors: E
authors: Stacher
authors: Christian
authors: C
authors: Gülly
authors: Franz
authors: F
authors: Quehenberger
authors: Susann
authors: S
authors: Stephan-Falkenau
authors: Jens
authors: J
authors: Kollmeier
authors: Andreas
authors: A
authors: Roth
authors: Thomas
authors: T
authors: Mairinger
authors: Helmut
authors: H
authors: Popper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D008875:Middle Aged; D000068437:Pemetrexed; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000235:genetics / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase / Q000235:genetics / Q000378:metabolism; D010997:Pleural Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D058978:Reduced Folate Carrier Protein / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D005971:Glutamates; D012333:RNA, Messenger; D058978:Reduced Folate Carrier Protein; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase