Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-fluorouracil
Journal
PLoS ONE
Journal Volume
6
Journal Issue
6
Pages
e21000
Date Issued
2011
Author(s)
Abstract
Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography-based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high-performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. 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 in bile with 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. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT. ? 2011 Hsieh et al.
SDGs
Other Subjects
fluorouracil; matrix metalloproteinase inhibitor; neutrophil collagenase; antineoplastic agent; cytokine; enzyme inhibitor; fluorouracil; neutrophil collagenase; animal experiment; area under the curve; article; cancer radiotherapy; controlled study; drug blood level; enzyme activity; enzyme blood level; enzyme release; high performance liquid chromatography; human; human cell; male; nonhuman; pelvis; protein analysis; radiation dose; rat; regulatory mechanism; adjuvant chemotherapy; animal; bile; blood; drug antagonism; drug effect; intracellular space; liver; metabolism; physiology; radiation exposure; solubility; Sprague Dawley rat; Rattus; Animals; Antineoplastic Agents; Bile; Chemotherapy, Adjuvant; Cytokines; Enzyme Inhibitors; Fluorouracil; Intracellular Space; Liver; Male; Matrix Metalloproteinase 8; Pelvis; Rats; Rats, Sprague-Dawley; Solubility
Type
journal article