Modulation of doxorubicin uptake by epinephrine in the VX-2 carcinoma

Abstract

The purpose of regional chemotherapy is to deliver maximal drug concentrations to localized unresectable tumors, to minimize systemic toxicity, and to improve tumor response to treatment. Manipulation of regional blood flow by vasoactive agents could further increase tumor drug levels. This study evaluates the effect of hepatic artery infusion of epinephrine on tumor and liver doxorubicin uptake. New Zealand White rabbits ( n = 17) were implanted with hepatic VX-2 carcinomas which were allowed to grow to 2–3 cm in diameter. Doxorubicin (3 mg/kg) ± [ 14C]doxorubicin (2.5 μCi) was given alone (controls) or following low- (5 μg) or high- (15–50 μg) dose epinephrine infusion into the hepatic artery. Heart, liver, and tumor were obtained 30 min after infusion for determination of doxorubicin concentration. The doxorubicin liver concentrations were similar in all three groups but tumor levels decreased from 26.6 ± 16.3 to 6.7 ± 2.8 and 6.6 ± 4.3 nmole/g in the epinephrine groups. Myocardial levels were reduced by the high-dose epinephrine (6.8 ± 2.2 nmole/g) when compared to controls (11.3 ± 2.1 nmole/g) or low-dose epinephrine (11.5 ± 1.8 nmole/g). The liver concentration of doxorubicin was not significantly affected by intraarterial epinephrine. The myocardial doxorubicin concentration was affected only by epinephrine doses sufficient to cause severe systemic vasoconstriction. The decrease in tumor doxorubicin concentration to low-dose (5 μg) and high-dose (15–50 μg) epinephrine suggests that intraarterial epinephrine limits doxorubicin uptake by tumor.