Correlation between tumour blood flow and fluorouracil distribution in a hypovascular liver metastasis model.
The poor response of colorectal liver metastases to fluorinated pyrimidine chemotherapy may be due to poor drug penetration into the tumour. Chemotherapy delivered by the blood to well perfused areas of tumour must reach less well perfused areas by diffusion. This study examined the relationship between intratumoural blood flow and drug uptake in a hypovascular liver metastasis animal model. We used a double isotope technique to examine the microdistribution of the blood flow tracer [125I]-iodoantipyrine (IAP) and fluorinated pyrimidine 5-[6-3H]-fluorouracil (5-FU) within intrahepatic, hypovascular HSN tumours. There was a significant fall (P < 10(-6)) in both IAP and 5-FU uptake between the liver/tumour edge and tumour centre which resulted in a significant covariation (P < 10(-5)) in tracer uptake with distance. The finding of a close covariation between blood flow and drug uptake in liver metastases suggested that 5-FU diffusion did not compensate for low 5-FU delivery in areas of poor tumour blood flow. The lower 5-FU levels in low compared with high areas of tumour blood flow could reduce the cytotoxic effect and increase the potential for development of drug resistance.
Burke
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Department of Academic Surgery, Leeds General Infirmary, UK. D.burke@leeds.ac.uk
Carnochan
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Glover
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Allen-Mersh
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TG
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000737:chemistry; D002138:Calibration; D015179:Colorectal Neoplasms / Q000473:pathology*; D005472:Fluorouracil / Q000493:pharmacokinetics*; D008113:Liver Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051381:Rats; D012039:Regional Blood Flow
D000964:Antimetabolites, Antineoplastic; D000983:Antipyrine; D005472:Fluorouracil; C008135:iodoantipyrine