Role of matrix metalloproteinase-8 in the modulation of systemic 5-fluorouracil pharmacokinetics by local irradiation.

Abstract

466 Background: Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. Methods: The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to the rats to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Results: Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased the AUC in bile in a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Conclusions: Local irradiation may modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. This unexpected influence is worthy of further investigation and for consideration in clinical practice of radiotherapy for cancer. No significant financial relationships to disclose.