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.


OBJECTIVE
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 microM [3H]5-FU, and the formation of [3H]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 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; 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.
Yee
L K
LK
(NCI-Navy Medical Oncology Branch), National Institutes of Health, Bethesda, MD 20889-5105.
Allegra
C J
CJ
Steinberg
S M
SM
Grem
J L
JL
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D004067:Digestive System Neoplasms / Q000097:blood / Q000188:drug therapy; D042943:Dihydrouracil Dehydrogenase (NADP); D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000201:enzymology; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism*; D010088:Oxidoreductases / Q000097:blood; D011994:Recombinant Proteins
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil