Potentiation of the cytostatic effect of melphalan on colorectal cancer hepatic metastases by infusion of buthionine sulfoximine (BSO) in the rat: enhanced tumor glutathione depletion by infusion of BSO in the hepatic artery.
OBJECTIVE
Glutathione (GSH) plays an important role in the resistance of tumors to cytostatics. Therefore, depletion of GSH by the GSH synthesis inhibitor buthionine sulfoximine (BSO) has been proposed to enhance the efficacy of certain anticancer agents. We studied the effect of BSO in rats bearing intrahepatically implanted tumors of the CC531 colorectal cancer cell line on the antitumor activity of melphalan (L-PAM). Since these liver tumors tend to derive most of their blood supply from the hepatic artery, we evaluated whether delivery of BSO into the hepatic artery would more selectively decrease GSH levels in the implanted tumor tissue as compared with normal liver and extrahepatic tissues.


METHODS
Tumor-bearing rats were treated with a 24-h continuous infusion of 0.375 mmol/ kg BSO via the jugular vein, immediately followed by a bolus L-PAM (15 micromol/kg; 4.5 mg/kg) infusion via the hepatic artery. Laparotomy was performed on day 14 and 28 after treatment for measurement of the liver tumors. For the evaluation of locoregional administration of BSO, a 24-h continuous infusion of 0.375 mmol/kg BSO was delivered into either the hepatic artery, the portal vein, or the jugular vein in freely moving rats and GSH levels in the tumor, liver, kidney, lung, heart, bone marrow, and blood were measured.


RESULTS
BSO infusion via the jugular vein increased the antitumor efficacy of L-PAM injected into the hepatic artery 2-fold as determined at 14 days after treatment. Although infusion of BSO via the hepatic artery depleted GSH more severely in the tumor as compared with jugular vein or portal vein administration, the additional effect was only slight (10%). No difference was observed in any other tissue.


CONCLUSIONS
GSH depletion increased the cytostatic efficacy of L-PAM 2-fold in vivo as determined at 14 days after treatment. Hepatic artery infusion of BSO translated into a statistically significant, but probably not therapeutically relevant, increase in tumor GSH depletion as compared with the other routes of BSO administration.
Department of Surgery, Leiden University Medical Center, The Netherlands. vahrmeyer@surgery.azl.nl
A L
AL
Vahrmeijer
J H
JH
van Dierendonck
J
J
Schutrups
C J
CJ
van de Velde
G J
GJ
Mulder
D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005978:Glutathione / Q000032:analysis*; D007261:Infusions, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000556:secondary*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D051381:Rats
D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan