Decreased Catabolism of Fluorouracil in Peripheral Blood Mononuclear Cells During Combination Therapy With Fluorouracil, Leucovorin, and Interferon α–2a

Abstract

Background : We previously reported that recombinant interferon α-2a (IFN α-2a) therapy was associated with a dose-dependent decrease in fluorouracil (5-FU) clearance. Purpose : In this study, we used peripheral blood mononuclear cells (PBMCs), which are responsive to IFNs, as surrogate tissue to determine whether the change in clearance might be explained by decrease in 5-FU catabolism during IFN α-2a therapy. Methods : The study population consisted of 45 patients with adenocarcinoma arising in the gastrointestinal tract. Thirty-seven patients received therapy containing IFN α-2a at a median dose of 5 million U/m ² per day (range, 1.7–7.5 million U/m ² per day) starting on day 1 and continuing through either day 7 or day 14 in conjunction with intravenous high-dose leucovorin (LV) followed by bolus 5-FU on days 2–6. Eight patients received the same schedule of 5-FU and LV daily for 5 days without IFN α-2a but with granulocyte-macrophage colony-stimulating factor starting on day 6 and ending at least 3 days prior to the start of the next cycle. Peripheral blood was collected during 70 cycles on days 1, 2, and 4 prior to the daily treatment with IFN α-2a + 5-FU + LV and during 19 cycles on days 1 and 4 prior to the daily treatment with 5-FU + LV without IFN α-2a. In a given patient cycle, matched samples were drawn at approximately the same time of day. PBMCs were isolated, and the intact cells were exposed to 4 μ M [ ³ H]5-FU, and the formation of [ ³ H]dihydrofluorouracil was determined by reverse-phase high-performance liquid chromatography. Results : In 47 matched patient cycles from IFN α-2a + 5-FU + LV-treated patients in which samples were available on days 1, 2, and 4, 5-FU catabolism decreased by 20% ( P₂ =.03) and 41% ( P₂ =.0001) from the baseline catabolic rate (2.5 ± 0.2 pmol/min per 10 ⁶ cells [mean ± SE]) on days 2 and 4, respectively. Using information from all paired samples, the mean change from baseline on day 2 was −0.4 ± 0.2 pmol/min per 10 ⁶ cells (n = 54; P₂ =.05), and the change from baseline on day 4 was −1.3 ± 0.3 pmol/min per 10 ⁶ cells (n = 63; P ₂ =.0001). In contrast, changes in 5-FU catabolism were not evident in the PBMCs of the reference population receiving 5-FU + LV without IFN α-2a. Conclusions : The magnitude of the change in 5-FU catabolism is similar to the magnitude of the decrease in 5-FU clearance in our previous study. These observations suggest that changes in 5-FU catabolism during therapy with IFN α-2a, 5-FU, and LV may account for the decreased 5-FU clearance. [J Natl Cancer Inst 84:1820–1825, 1992]