Decreased catabolism of fluorouracil in peripheral blood mononuclear cells during combination therapy with fluorouracil, leucovorin, and interferon α-2a

Lorrin K. Yee, Carmen J. Allegra, Seth M. Steinberg, Jean L. Grem

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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/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 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 μM [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 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 106 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 106 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 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]

Original languageEnglish (US)
Pages (from-to)1820-1825
Number of pages6
JournalJournal of the National Cancer Institute
Volume84
Issue number23
DOIs
StatePublished - Feb 2 1992

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Leucovorin
Fluorouracil
Interferons
Blood Cells
Therapeutics
Reverse-Phase Chromatography
Granulocyte-Macrophage Colony-Stimulating Factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Decreased catabolism of fluorouracil in peripheral blood mononuclear cells during combination therapy with fluorouracil, leucovorin, and interferon α-2a. / Yee, Lorrin K.; Allegra, Carmen J.; Steinberg, Seth M.; Grem, Jean L.

In: Journal of the National Cancer Institute, Vol. 84, No. 23, 02.02.1992, p. 1820-1825.

Research output: Contribution to journalArticle

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title = "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/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 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 μM [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 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 106 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 106 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 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]",
author = "Yee, {Lorrin K.} and Allegra, {Carmen J.} and Steinberg, {Seth M.} and Grem, {Jean L.}",
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T1 - Decreased catabolism of fluorouracil in peripheral blood mononuclear cells during combination therapy with fluorouracil, leucovorin, and interferon α-2a

AU - Yee, Lorrin K.

AU - Allegra, Carmen J.

AU - Steinberg, Seth M.

AU - Grem, Jean L.

PY - 1992/2/2

Y1 - 1992/2/2

N2 - 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/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 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 μM [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 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 106 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 106 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 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]

AB - 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/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 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 μM [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 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 106 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 106 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 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]

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