The cytotoxic effect of trastuzumab in combination with oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2 (HER2)-overexpressing human pancreatic cancer cell line TRG in vitro and in vivo was investigated. HER2 expression in TRG was analyzed by RT-PCR and flow cytometry. For in vitro experiments, 5-fluorouracil (5-FU) was used instead of S-1. In vivo studies were conducted with TRG xenografts in athymic mice. Trastuzumab (10 mg/kg) was administered intraperitoneally once a week for 4 weeks. S-1 (10 mg/kg) was administered orally 5 days a week for 4 weeks. The results showed that TRG cells were positive for HER2 mRNA and overexpressed HER2 protein. Either trastuzumab or 5-FU concentration-dependently inhibited the growth of TRG cells. The combination of trastuzumab and 5-FU resulted in a significant inhibition of growth of TRG cells compared to either agent alone (P<0.001). Incubation of TRG cells with peripheral blood mononuclear cells after treatment with trastuzumab enhanced the antiproliferative effect of trastuzumab, which could be the result of antibodydependent cellular cytotoxicity. The combination of trastuzumab and S-1 resulted in a significant reduction in xenograft volume compared to each agent alone (P<0.0001). In conclusion, this study showed that combination therapy with trastuzumab and S-1 may be effective for HER2-overexpressing pancreatic cancer patients.

Using a monoclonal antibody to bromodeoxyuridine, we studied the cell kinetics of human hepatocellular carcinoma, liver cirrhosis, chronic active hepatitis and alcoholic liver fibrosis. Specimens were taken either by biopsy or surgery and immediately incubated with 0.1% bromodeoxyuridine solution at 37 degrees C for 45 min. After in vitro labeling, the bromodeoxyuridine taken up by the nuclei of S-phase cells was determined by the avidin-biotin-peroxidase complex method, using an anti-bromodeoxyuridine monoclonal antibody as the first antibody. The number of positive nuclei in 1,000 hepatic cells was counted, and the bromodeoxyuridine labeling index was expressed per thousand. The mean bromodeoxyuridine labeling index +/- S.D. of the cancerous portion of hepatocellular carcinoma, the noncancerous portion of hepatocellular carcinoma, liver cirrhosis, chronic active hepatitis and alcoholic liver fibrosis were 64.1 +/- 31.3, 33.6 +/- 14.4, 23.2 +/- 20.8, 9.1 +/- 6.1 and 21.6 +/- 13.0, respectively. The mean bromodeoxyuridine labeling index of the hepatocellular carcinoma cancerous portion was statistically higher than that of any other group. There was no statistical difference by the t test or the Wilcoxon test between the noncancerous portion of hepatocellular carcinoma and liver cirrhosis, and these two groups were proved interdependent by chi 2 test (Fisher's exact test), whether they were subdivided by bromodeoxyuridine labeling index greater than or equal to 10 or not. Bromodeoxyuridine labeling index was not significantly correlated with the usual biochemical parameters such as serum AST, ALT, gamma-GTP, alkaline phosphatase, lactate dehydrogenase, cholinesterase, albumin, and alpha-fetoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)

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