title: Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-Fluorouracil.
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.
authors.affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chen-Hsi
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Liu
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Hsieh
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Tai
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Wang
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001646:Bile / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008099:Liver / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D010388:Pelvis / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020784:Matrix Metalloproteinase 8; D005472:Fluorouracil