Combined effects of docetaxel and fluoropyrimidines on tumor growth and expression of interleukin-6 and thymidine phosphorylase in breast cancer xenografts

Purpose: Although several combination treatments with docetaxel and other antitumor agents have been tested in experimental and clinical studies, their synergistic effects are still ill-defined. The degree of synergism between docetaxel and two oral fluoropyrimidines, tegafur and 5′-deoxy-5-fluorouridine (5′-dFUrd), was investigated in the KPL-4 human breast cancer xenograft model. Methods: Because this KPL-4 cell line secretes interleukin-6 (IL-6) and induces cachexia, the effects of the combined treatment on serum IL-6 levels and cachectic markers were investigated. In addition, the expression levels of thymidine phosphorylase (dThdPase), a key enzyme for converting 5′-dFUrd to 5-fluorouracil, were determined. Female nude mice bearing KPL-4 tumors were treated orally with 5′-dFUrd (60 mg/kg, five times a week) or tegafur (100 mg/kg, five times a week) and by intraperitoneal injection of docetaxel (5 or 10 mg/kg, once a week). Results: Although docetaxel (5 mg/kg) alone did not decrease either tumor growth or serum IL-6 levels, docetaxel (5 mg/kg) plus 5′-dFUrd or tegafur enhanced tumor growth inhibition and decreased serum IL-6 levels more than 5′-dFUrd or tegafur alone. Docetaxel (5 mg/kg) alone slightly increased the percentage of dThdPase-positive tumor cells, but the combined treatment with docetaxel plus 5′-dFUrd or tegafur significantly decreased the percentage of dThdPase-positive cells in the KPL-4 tumors. Conclusion: These findings indicate that docetaxel may stimulate dThdPase expression in tumor tissues and may enhance the antitumor activity of oral fluoropyrimidines. In addition, combined treatment with docetaxel and oral fluoropyrimidines may decrease serum IL-6 levels and may ameliorate IL-6-induced cancer cachexia.