title: Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy.
abstract: BACKGROUND
  Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for treatment of metastatic colorectal cancer (CRC). Increased expression of thymidylate synthetase (TS) in CRC metastases has been proposed to be an important mechanism of resistance to fluoropyrimidine-based chemotherapy.
  
  
  METHODS
  The present study investigated whether TS mRNA levels in liver metastases of 20 CRC patients before treatment with FUDR by hepatic arterial infusion (HAI) correlated with frequency of clinical response or survival duration.
  
  
  RESULTS
  Median survival duration of patients with TS mRNA levels above and below the median was 15 and 18 months, respectively (p > 0.05). Clinical response was achieved in 40% of patients with low TS mRNA levels, but in only 20% of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also measured for liver metastases of 7 of the patients that did not achieve a clinical response. A statistically significant increase in expression of TS mRNA was observed for liver metastases resistant to chemotherapy (21 +/- 14) in comparison to liver metastases of the same patients before chemotherapy (8 +/- 4) (p = 0.03).
  
  
  CONCLUSIONS
  This is the first report to demonstrate increased TS expression in liver metastases from CRC patients resistant to fluoropyrimidine based chemotherapy. These findings are consistent with previous studies indicating that increased TS expression is associated with resistance to fluoropyrimidine-based chemotherapy.
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, PN, Italy. mlibra@unict.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Navolanic
authors.forename: Renato
authors.initials: R
authors.lastname: Talamini
authors.forename: Erica
authors.initials: E
authors.lastname: Cecchin
authors.forename: Franca
authors.initials: F
authors.lastname: Sartor
authors.forename: Salvatore
authors.initials: S
authors.lastname: Tumolo
authors.forename: Sara
authors.initials: S
authors.lastname: Masier
authors.forename: Salvatore
authors.initials: S
authors.lastname: Travali
authors.forename: Mauro
authors.initials: M
authors.lastname: Boiocchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D015179:Colorectal Neoplasms; D019008:Drug Resistance, Neoplasm; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D005467:Floxuridine; D013940:Thymidylate Synthase