Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy.
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.
Libra
Massimo
M
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, PN, Italy. mlibra@unict.it
Navolanic
Patrick M
PM
Talamini
Renato
R
Cecchin
Erica
E
Sartor
Franca
F
Tumolo
Salvatore
S
Masier
Sara
S
Travali
Salvatore
S
Boiocchi
Mauro
M
Toffoli
Giuseppe
G
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*
D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D005467:Floxuridine; D013940:Thymidylate Synthase