Abstract
BackgroundA synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans.MethodsA total of 128 consecutive blood samples were collected from eight patients with advanced breast cancer receiving paclitaxel weekly at a dose of 80 mg/m2. To assess the expression of TP in blood cells, samples were collected prior to first therapy, at the end of infusion, and up to 15 days thereafter. This procedure was repeated during the sixth application of paclitaxel. After isolation of the peripheral mononuclear blood cells, the expression of TP was assessed by ELISA. In parallel, paclitaxel level in plasma was evaluated at three selected time points as pharmacokinetic control parameter.ResultsPaclitaxel concentrations at the end of infusion did not change significantly from week 1 to week 6. The expression of TP in peripheral mononuclear blood cells decreased significantly after infusion below pretherapeutic values (p = 0.023; n = 8). After the nadir on day 3, the expression of TP increased moderately returning to baseline levels within one week. The overall picture in week 6 was similar to week 1. Using a trend analysis, neither a short-term nor a long-term induction of TP was observed.ConclusionTP in peripheral mononuclear blood cells was hardly regulated under therapy with paclitaxel. Therefore, no increased haematotoxicity due to TP upregulation is expected from the combination of taxanes and capecitabine.
Highlights
A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil
Thymidine phosphorylase In eight paclitaxel naive patients, the expression of thymidine phosphorylase in peripheral mononuclear blood cells temporarily decreased under infusion with paclitaxel equilibrating within 24 h to enzyme levels observed prior to therapy (Figure 1)
In the 48 hours, these levels decreased to thymidine phosphorylase levels significantly below pretherapeutic values resulting in a TP nadir on day 3 (p = 0.023)
Summary
A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. This hypothesis has not been investigated in humans. Taxanes are a group of compounds that interact with the β subunit of tubulin and induce tubulin polymerization interfering with the normal balance between polymerization and its contrary, depolymerisation. This mechanism eventually leads to the arrest in the G2/M phase of the cell cycle with subsequent cell death [1]
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