Toxicity study of hepatic artery infusion chemotherapy with massive dose FUDR in rats

Hepatic artery infusion (HAI) of fluoroudeoxyuridine (FUDR) has been shown to be effective in the treatment of liver metastases from colorectal cancer. However, local toxicity is the most serious limitation of this therapy. The aetiology of HAI toxicity remains unclear. To assess the HAI toxicity, forty-eight non-tumour-bearing, healthy BD-IX rats were randomized to control or treatment groups. The control group (n = 24) received heparinized saline alone (200 u heparin kg-1 day-1) and the treatment group (n = 24) received 6.7 mg FUDR kg-1 day-1 (equivalent to the human dose of 1.0 kg-1 day-1) via HAI for 28 days. Blood samples were collected for haematologic and biochemical analysis twice a week (on days 3 and 7). Toxicity was evaluated by determination of mortality, body weight, white blood cell (WBC) count, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin and blood urea nitrogen (BUN), and creatinine. No significant differences in WBC, SGOT, BUN and creatinine levels were found between the group receiving FUDR treatment and the control group. Significantly higher total bilirubin levels, mortality and body weight loss were found in the FUDR-treated group than in the control group. A multivariate analysis revealed that total bilirubin level was the only significant predictor of mortality in the FUDR treatment group. These results suggested that biliary tract damage seems to be the principal toxicity of HAI FUDR chemotherapy.