DECREASED CATABOLISM OF FLUOROURACIL IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS DURING COMBINATION THERAPY WITH FLUOROURACIL, LEUCOVORIN, AND INTERFERON ALPHA-2A

Background: We previously reported that recombinant interferon alpha-2a (IFN alpha-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 alpha-2a therapy. Methods: The study population consisted of 45 patients with adenocarcinoma arising in the gastrointestinal tract. Thirty-seven patients received therapy containing IFN alpha-2a at a median dose of 5 million U/m2 per day (range, 1.7-7.5 million U/m2 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 alpha-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 alpha-2a + 5-FU + LV and during 19 cycles on days 1 and 4 prior to the daily treatment with 5-FU + LV without IFN alpha-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 muM [H-3]5-FU, and the formation of [H-3]dihydrofluorouracil was determined by reverse-phase high-performance liquid chromatography. Results: In 47 matched patient cycles from IFN alpha-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 106 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; P2 = .0001). In contrast, changes in 5-FU catabolism were not evident in the PBMCs of the reference population receiving 5-FU + LV without IFN alpha-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 alpha-2a, 5-FU, and LV may account for the decreased 5-FU clearance.