Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed.
OBJECTIVE
The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS) and other genes for response to raltitrexed (RTX).


METHODS
Twenty-five patients with metastatic colorectal cancer received RTX 3 mg/m(2) 3-weekly. Pretreatment tumor biopsies were analyzed for TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), folylpolyglutamate synthetase, and reduced folate carrier mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody.


RESULTS
Twenty patients were evaluable for response and gene expression. Six of 20 (30%) achieved a partial response. Median TS/beta-actin was 5.7 x 10(3) (range, 2.2-42 x 10(3)). Median TS/beta-actin was 3.7 x 10(3) in responding patients and 6.1 x 10(3) in nonresponders (P = 0.048). Five of 6 patients with TS/beta-actin </=4.1 x 10(3) and 1 of 14 with higher values responded (P = 0.002). Overall survival was 21.7 months in patients with TS/beta-actin </=4.1 x 10(3) and 5.7 months in patients with higher values (P = 0.013). No correlations were seen between expression of TP, DPD, reduced folate carrier, or folylpolyglutamate synthetase mRNA and response or survival. Weak TS staining was seen in 10 of 21 tumors evaluable for immunohistochemistry, including 5 responders All 4 of the patients with both weak staining and TS/beta-actin </=4.1 x 10(3) responded.


CONCLUSIONS
High TS mRNA expression predicts nonresponse to RTX. By contrast with 5-fluorouracil, high levels of TP and DPD mRNA are not associated with RTX resistance. Limited genomic fingerprinting could optimize single-agent therapy, allowing combinations to be reserved for high TS-expressing patients or for treatment failures, with potential reductions in toxicity and cost.
Farrugia
David C
DC
Section of Medicine and Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Ford
Hugo E R
HE
Cunningham
David
D
Danenberg
Kathleen D
KD
Danenberg
Peter V
PV
Brabender
Jan
J
McVicar
A David
AD
Aherne
G Wynne
GW
Hardcastle
Anthea
A
McCarthy
Keith
K
Jackman
Ann L
AL
D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000627:therapeutic use*; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D011237:Predictive Value of Tests; D014176:Protein Biosynthesis; D011799:Quinazolines / Q000097:blood / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013876:Thiophenes / Q000097:blood / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D014158:Transcription, Genetic; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed