Impact of platinum complexes on dihydropyrimidine dehydrogenase activity in 5-fluorouracil-treated patients

N. Magné1,2, X. Pivot3, M. C. Etienne-Grimaldi2, E. François2, N. Renée2, A. Thyss2, M. Schneider2, F. Demard2 and G. Milano*,2

1 Department of Radiotherapy, Institut Jules Bordet, Brussels, Belgium; 2 Oncopharmacology Unit, Centre Antoine Lacassagne, Nice; 3 Department of Medical Oncology, CHU Jean Minjoz, Besançon, France

*E-mail: gerard.milano@cal.nice.fnclcc.fr

The association cisplatin–5-fluorouracil (5-FU) in head and neck cancer [1], and the more recent combination between oxaliplatin (OXA) and 5-FU in advanced colorectal cancer [2], have largely proved their clinical efficacy. The origin of the pharmacological interaction between these associated drugs has not been fully elucidated. The enzyme dihydropyrimidine dehydrogenase (DPD) controls the catabolic route of 5-FU and thus influences 5-FU pharmacokinetics and pharmacodynamics [3]. Recent pharmacokinetic studies have suggested that OXA may inhibit 5-FU catabolism. This observation advocates a possible impact of OXA on DPD activity [4]. We recently conducted the following prospective clinical study to evaluate the impact of platinum complexes on DPD activity.

Twenty-two cancer patients who had not received prior chemotherapy treatment (13 head and neck cancer patients and nine advanced colorectal cancer patients) were included (19 men, three women). Mean age was 59 years (range 40–77). Most patients (73%) had a performance status <2. Cisplatin (80–100 mg/m2) in head and neck cancer patients and OXA (60–100 mg/m2) in colorectal cancer patients were given in association with 5-FU as previously described [1, 2]. Two blood samples were taken in the morning between 9.00 and 11.00 a.m., in order to limit the impact of the circadian influence reported for DPD activity; one just before starting platinum complex administration (day 1), and the second 24 h later (i.e. after platinum complexes administration and before starting administration of 5-FU). This was done during the first cycle of treatment. DPD activity was measured in peripheral blood mononuclear cells (PBMC) as previously described [5].

Dihydropyrimidine dehydrogenase activity before treatment ranged from 80 to 590 pmol/min/mg protein (mean 280, median 270). This range of DPD distribution, as well as the mean and median values, compare well to previous population studies of PBMC DPD activity in cancer patients [6]. PBMC DPD activity significantly decreased after platinum administration (Figure 1; paired-sample t-test, P = 0.010): the mean decrease in PBMC DPD activity was 73 pmol/min/mg protein (95% confidence interval 13.7–93.09). DPD decreased in 15/22 patients (68%; six out of nine patients with OXA and nine out of 13 patients with cisplatin). The DPD decrease was not related to the type of platinum complex administered (ANOVA, P = 0.60). In five patients, it was possible to perform a follow-up of DPD during the treatment course (four cycles of cisplatin–5-FU). All five had a DPD decrease that was maintained during this observation period.



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Figure 1. Impact of the administration of platinum derivatives (cisplatin, oxaliplatin) on dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (22 patients). There was a 24-h interval between the two DPD measurements.

 
These clinically-based observations concur with previous pharmacokinetic observations [4] and may have several pharmacological and clinical implications. First, they point to a possible pharmacological explanation for at least part of the synergistic interaction between platinum complexes and 5-FU, which could be based on DPD inhibition. Indeed, DPD inhibition at the target level may reduce the loss of 5-FU by a DPD-mediated catabolic route. Secondly, the data also suggest that patients with relatively low intrinsic DPD activity may be placed at risk of marked toxicity when receiving a platinum complex–5-FU combination. The mechanistic origin of the DPD inhibition remains to be elucidated.

N. Magné1,2, X. Pivot3, M. C. Etienne-Grimaldi2, E. François2, N. Renée2, A. Thyss2, M. Schneider2, F. Demard2 & G. Milano2*

1Department of Radiotherapy, Institut Jules Bordet, Brussels, Belgium; 2Oncopharmacology Unit, Centre Antoine Lacassagne, Nice; 3Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz, Besançon, France (*E-mail: gerard.milano@cal.nice.fnclcc.fr)

References

1. Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control 2002; 9: 387–399.[Medline]

2. Holen KD, Saltz LB. New therapies, new directions: advances in the systemic treatment of metastatic colorectal cancer. Lancet Oncol 2001; 2: 290–297.[CrossRef][Medline]

3. Milano G, McLeod HL. Can dihydropyrimidine dehydrogenase impact 5-fluorouracil based treatment? Eur J Cancer 2000; 36: 37–42.[CrossRef][ISI][Medline]

4. Boisdron-Celle M, Craipeau C, Brienza S et al. Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences. Cancer Chemother Pharmacol 2002; 49: 235–243.[CrossRef][ISI][Medline]

5. Fleming R, Milano G, Thyss A et al. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 1992; 52: 2899–2902.[Abstract]

6. Etienne MC, Lagrange JL, Dassonville O et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994; 12: 2248–2253.[Abstract]





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