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Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the
A B Van Kuilenburg1, H van Lenthe, M J Blom
1Academic Medical Center, University of Amsterdam, Emma Children's Hospital, and Department of Clinical Chemistry, The Netherlands.
Abstract:
Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency.
Insights
Dihydropyrimidine dehydrogenase (DPD) activity in blood cells varies significantly due to monocyte content. This variability hinders the accurate detection of DPD deficiency in patients undergoing 5-fluorouracil chemotherapy.
Area of Science:
- Pharmacology
- Biochemistry
- Oncology
Background:
- Dihydropyrimidine dehydrogenase (DPD) is crucial for metabolizing 5-fluorouracil (5FU), a widely used chemotherapy drug.
- DPD deficiency can lead to severe toxicity and reduced treatment efficacy.
- Assessing DPD activity in peripheral blood mononuclear cells (PBM cells) is standard for identifying patients with DPD deficiency.
Purpose of the Study:
- To investigate the cellular distribution of DPD activity within PBM cells.
- To determine the impact of cellular composition on DPD activity measurements in PBM cells.
- To understand the variability in DPD activity and its implications for diagnosing DPD deficiency.
Main Methods:
- Quantification of DPD activity in different blood cell types (monocytes, lymphocytes, granulocytes, platelets, erythrocytes).
- Analysis of PBM cell composition, specifically the percentage of monocytes.
- Correlation analysis between DPD activity in PBM cells and monocyte percentage.
Main Results:
- DPD activity is highest in monocytes, followed by lymphocytes, granulocytes, and platelets; erythrocytes show no significant activity.
- DPD activity in PBM cells is intermediate, reflecting the combined activity of its cellular components.
- Cancer patients exhibited a higher monocyte percentage in PBM cells compared to healthy volunteers.
- A strong positive correlation exists between PBM cell DPD activity and monocyte percentage, leading to significant inter- and intrapatient variability.
Conclusions:
- Monocyte abundance significantly influences measured DPD activity in PBM cells.
- The high inter- and intrapatient variability caused by monocyte content complicates the reliable detection of partial DPD deficiency.
- Current methods for assessing DPD deficiency using PBM cells may require refinement to account for cellular composition variations.