title: Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.
abstract: BACKGROUND
  Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells.
  
  
  METHODS
  We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis.
  
  
  RESULTS
  The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed.
  
  
  CONCLUSIONS
  A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takezawa
authors.forename: I
authors.initials: I
authors.lastname: Okamoto
authors.forename: W
authors.initials: W
authors.lastname: Okamoto
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Sakai
authors.forename: S
authors.initials: S
authors.lastname: Tsukioka
authors.forename: K
authors.initials: K
authors.lastname: Kuwata
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000068437:Pemetrexed; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase