Patterns of elevation of plasma 2'-deoxyuridine, a surrogate marker of thymidylate synthase (TS) inhibition, after administration of two different schedules of 5-fluorouracil and the specific TS inhibitors raltitrexed (Tomudex) and ZD9331.
5-Fluorouracil (5-FU) exerts cytotoxic effects through inhibition of thymidylate synthase (TS) and incorporation of metabolites into RNA. TS inhibition may be greater for infusional 5-FU, with bolus regimens more likely to cause RNA effects. Elevation of plasma 2'-deoxyuridine (dUrd) is a surrogate marker of TS inhibition. Nineteen patients were treated with continuous infusion (CI) 5-FU 300mg/m(2)/day or bolus 5-FU 425mg/m(2)/day plus leucovorin (LV) 20mg/m(2)/day days 1-5. Pretreatment (day 1) and day 2, 3, 4, 5, 8, 15, 22, and 29 plasma samples were assayed for dUrd by reverse-phase high-performance liquid chromatography. In patients treated with bolus 5-FU/LV, dUrd elevation at 24 and 48 h was 235 +/- 125 and 254 +/- 119%, respectively, falling to 138 +/- 58%, 156 +/- 89%, and 92 +/- 25% on days 8, 15, and 22, respectively. dUrd elevation with CI 5-FU was 229 +/- 86% at 24 h and 239 +/- 86, 240 +/- 98%, and 255 +/- 109% at days 15, 22, and 29, respectively. Duration of dUrd elevation was generally less than 8 days for bolus 5-FU/LV. A single dose of raltitrexed (3 mg/m(2)) gave a similar profile to this regimen. ZD9331 (130 mg/m(2), days 1 and 8) gave dUrd elevation for 14 of 21 days, with some recovery prior to day 8. Thus, both 5-FU regimens inhibit TS, and prolonged TS inhibition is achieved by CI 5-FU without significant toxicity. This suggests that the mechanism of antiproliferative toxicity from bolus 5-FU/LV is partly non-TS mediated. These results clarify underlying pharmacodynamic processes and could guide scheduling of 5-FU and TS inhibitors.
Ford
Hugo E R
HE
Cancer Research Campaign Centre for Cancer Therapeutics at the Institute of Cancer Research and Royal Marsden National Health Service Trust, Sutton, Surrey, SM2 5NG.
Mitchell
Fraser
F
Cunningham
David
D
Farrugia
David C
DC
Hill
Mark E
ME
Rees
Charlotte
C
Calvert
A Hilary
AH
Judson
Ian R
IR
Jackman
Ann L
AL
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D003857:Deoxyuridine / Q000097:blood*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D011799:Quinazolines / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; C094299:ZD 9331; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil; D003857:Deoxyuridine