Changes in thymidylate synthase mRNA in blood leukocytes from patients with colorectal cancer after bolus administration of 5-fluorouracil.
5-fluorouracil (5-FU) is considered the standard antineoplastic drug of choice for metastatic colorectal cancer. It has been suggested that 5-FU administered as bolus infusion is cytotoxic mainly through an RNA damaging effect. We investigated the effect of i.v. bolus 5-FU 500-600 mg/m2 on the 5-FU target enzyme, thymidylate synthase (TS) mRNA, in blood leukocytes before and after courses 1 and 3 in 21 patients with colorectal cancer. TS mRNA expression was quantified using an RT-PCR assay with an internal RNA standard. Median TS mRNA expression decreased significantly 30 min after course no. 1 (p = 0.004), and both 15 min and 30 min after course 3 (p = 0.01). After course 1, the median TS mRNA expression decreased by 31% and after course 3 by 24%. Pharmacokinetic parameters were similar for individual patients during the two courses but did not correlate with the degree of TS mRNA inhibition. The present results indicate that TS mRNA in blood leukocytes may be an early indicator of an RNA damaging effect after i.v. bolus infusion of 5-FU.
Ehrnrooth
E
E
Department of Oncology, Aarhus University Hospital, Denmark. evae@dadlnet.dk
Sørensen
B
B
Poulsen
J H
JH
Sørensen
B S
BS
von der Maase
H
H
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects*
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil