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Molecular Oncology, Markers, Clinical Correlates |
Cancer Research Campaign Centre for Cancer Therapeutics at the Institute of Cancer Research and Royal Marsden National Health Service Trust, Sutton, Surrey, SM2 5NG; St Bartholemew’s Hospital, London EC2, ECIA 7BE; and Cancer Research Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, NE4 6BE United Kingdom
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/m2/day or bolus 5-FU 425mg/m2/day plus leucovorin (LV) 20mg/m2/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/m2) gave a similar profile to this regimen. ZD9331 (130 mg/m2, 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.
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