Vasopressin selectively increases 5-fluorouracil uptake by colorectal liver metastases following hepatic artery bolus infusion.
BACKGROUND
Poor drug uptake secondary to the hypovascularity of colorectal liver metastases may partially explain their limited response to hepatic artery chemotherapy. Vasoconstrictors can increase tumor perfusion but their effect on drug uptake has not been well-characterized. The aim of this study was to determine whether vasopressin could selectively increase tumor uptake of 5-FU.


METHODS
A syngeneic rat model of colorectal liver metastases was used. Control group rats underwent a 60-s hepatic artery infusion of 14C-5-FU (30 mCi/150 microL). Treatment group rats had vasopressin (60 mIU/kg, dose determined in pilot study) added to the 14C-5-FU infusion. Mean systemic arterial pressure was minimally affected. Tumor:liver (T/L UR) and tumor center:periphery (C/P UR) 5-FU uptake ratios were determined using quantitative autoradiography techniques. Differences in tumor size (< or > 4 mm) and location (superficial vs deep) were accounted for. Statistical analysis was by repeated measures ANOVA (P = 0.01 significant).


RESULTS
A total of 161 tumors in 18 rats was analyzed. T/L URs were significantly higher in the treatment group compared to controls for tumors <4 mm (1.72 +/- 0.14 vs 0.70 +/- 0.16, P <0.001), tumors >4 mm (0.99 +/- 0.15 vs 0.45 +/- 0.16, P = 0.01), deep tumors (1.17 +/- 0.13 vs 0.68 +/- 0.15, P = 0.01), and superficial tumors (1.54 +/- 0. 15 vs 0.47 +/- 0.17, P <0.001). C/P URs did not differ significantly between the groups.


CONCLUSIONS
The results of this study show that vasopressin selectively enhances the uptake of 5-FU by colorectal liver metastases in a rat model of hepatic artery infusion. This may represent a promising strategy for improving tumor response rates and patient survival.
Dietz
D W
DW
Department of General Surgery, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, 44195, USA.
Casillas
S
S
Jones
S C
SC
Milsom
J W
JW
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006499:Hepatic Artery; D007269:Injections, Intra-Arterial; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014667:Vasopressins / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D005472:Fluorouracil