Interleukin-2 as a modulator of 5-fluorouracil in hepatic arterial immunochemotherapy for liver metastases.
OBJECTIVE
Hepatic arterial infusion of interleukin-2-based immunochemotherapy has yielded a high response rate (> 75%) in patients with unresectable liver metastases. In order to clarify the mechanisms that underlie the apparent benefit of combination treatment, the role of IL-2 as a modulator of 5-fluorouracil metabolism was investigated.


METHODS
A single dose of 5-fluorouracil (50 mg/kg) with or without IL-2 (3500 Japan Reference Units/kg) was given via the hepatic artery to rats bearing liver metastases. Thirty minutes later samples of liver metastatic foci or surrounding normal liver tissue were removed for the measurement of thymidylate synthase, thymidine kinase and dihydropyrimidine dehydrogenase activity, and 5-fluorouracil content.


RESULTS
5-fluorouracil levels in tumor were significantly higher than in normal liver. Although the addition of IL-2 reduced 5-fluorouracil levels in both tumor and normal liver tissues by the activation of dihydropyrimidine dehydrogenase, the ratio of tumor/normal liver 5-fluorouracil levels was unchanged. Both thymidylate synthase and thymidine kinase activities were significantly inhibited in tumor tissue when the combination of 5-fluorouracil and IL-2 was administered.


CONCLUSIONS
IL-2 increases 5-fluorouracil cytotoxicity through the inhibition of thymidylate synthase/thymidine kinase activities in the hepatic arterial infusion.
Okuno
K
K
First Department of Surgery, Kinki University School of Medicine, Osaka-sayama, Japan. okuno@surg1.med.kindai.ac.jp
Hirai
N
N
Takemoto
Y
Y
Kawai
I
I
Yasutomi
M
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D007261:Infusions, Intra-Arterial; D007376:Interleukin-2 / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D007376:Interleukin-2; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D005472:Fluorouracil