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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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The cytokines respond to irradiation (RT) and 5-fluorouracil (5-FU) in plasma for control, RT 2 Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU groups.(A) The level of transforming growth factor beta 1 (TGF-β1) in plasma. (B) The level of tumor necrosis factor alpha (TNF-α) in plasma. Each group's data was collected from five rats.
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pone-0021000-g003: The cytokines respond to irradiation (RT) and 5-fluorouracil (5-FU) in plasma for control, RT 2 Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU groups.(A) The level of transforming growth factor beta 1 (TGF-β1) in plasma. (B) The level of tumor necrosis factor alpha (TNF-α) in plasma. Each group's data was collected from five rats.

Mentions: Compared with the control group, there were no significant differences between the RT 2Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU group in the levels of transforming growth factor-beta 1 (TGF-β1) and tumor necrosis factor α (TNF-α) (Fig. 3A and 3B).


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)

The cytokines respond to irradiation (RT) and 5-fluorouracil (5-FU) in plasma for control, RT 2 Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU groups.(A) The level of transforming growth factor beta 1 (TGF-β1) in plasma. (B) The level of tumor necrosis factor alpha (TNF-α) in plasma. Each group's data was collected from five rats.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0021000-g003: The cytokines respond to irradiation (RT) and 5-fluorouracil (5-FU) in plasma for control, RT 2 Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU groups.(A) The level of transforming growth factor beta 1 (TGF-β1) in plasma. (B) The level of tumor necrosis factor alpha (TNF-α) in plasma. Each group's data was collected from five rats.
Mentions: Compared with the control group, there were no significant differences between the RT 2Gy alone, 5-FU alone, RT 0.5 Gy followed by 5-FU and RT 2 Gy followed by 5-FU group in the levels of transforming growth factor-beta 1 (TGF-β1) and tumor necrosis factor α (TNF-α) (Fig. 3A and 3B).

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