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Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-Fluorouracil.

Hsieh CH, Liu CY, Hsieh YJ, Tai HC, Wang LY, Tsai TH, Chen YJ - PLoS ONE (2011)

Bottom Line: Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment.A high-performance liquid chromatography system was used to measure 5-FU in the blood.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

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.

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Related in: MedlinePlus

Intracellular 5-fluorouracil (5-FU) levels for 50 µM 5-FU treated HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) with or without 10 µg/mL recombinant MMP-8 by high performance liquid chromatography.
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pone-0021000-g005: Intracellular 5-fluorouracil (5-FU) levels for 50 µM 5-FU treated HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) with or without 10 µg/mL recombinant MMP-8 by high performance liquid chromatography.

Mentions: We examined the role of recombinant MMP-8 on intracellular concentration of 5-FU in HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) without receiving radiation. There were no significant effect on the AUC of 5-FU between the recombinant MMP-8 plus 5-FU and 5-FU alone groups (Fig. 5). We found that recombinant MMP-8, not induced by irradiation, will not influence intracellular concentration of 5-FU in liver cells, mimicking a pharmacokinetic changes at cellular level.


Matrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-Fluorouracil.

Hsieh CH, Liu CY, Hsieh YJ, Tai HC, Wang LY, Tsai TH, Chen YJ - PLoS ONE (2011)

Intracellular 5-fluorouracil (5-FU) levels for 50 µM 5-FU treated HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) with or without 10 µg/mL recombinant MMP-8 by high performance liquid chromatography.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111455&req=5

pone-0021000-g005: Intracellular 5-fluorouracil (5-FU) levels for 50 µM 5-FU treated HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) with or without 10 µg/mL recombinant MMP-8 by high performance liquid chromatography.
Mentions: We examined the role of recombinant MMP-8 on intracellular concentration of 5-FU in HepG2 (Human liver tumor-derived cells possessing biochemical profiles characteristic of normal hepatocytes) without receiving radiation. There were no significant effect on the AUC of 5-FU between the recombinant MMP-8 plus 5-FU and 5-FU alone groups (Fig. 5). We found that recombinant MMP-8, not induced by irradiation, will not influence intracellular concentration of 5-FU in liver cells, mimicking a pharmacokinetic changes at cellular level.

Bottom Line: Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment.A high-performance liquid chromatography system was used to measure 5-FU in the blood.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

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.

Show MeSH
Related in: MedlinePlus