Immunohistochemical Demonstration of Dihydropyrimidine Dehydrogenase in Normal and Cancerous Tissues

Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Previous studies have suggested that high enzyme activities and mRNA levels of DPD are involved in the resistance of cancers to 5-FU. For immunohistochemically demonstrating the tumor resistance to 5-FU, we determined the most suitable and reproducible condition of antigen retrieval for DPD localization in formalin-fixed, paraffin-embedded sections, and analyzed DPD expression in various types of normal and cancerous tissues. Pressure cooking in ethylenediaminetetraacetic acid, pH 8.0, was the best choice for retrieving the antigenicity of DPD. In normal tissues, DPD immunoreactivity was consistently detected in squamous epithelia, hepatocytes, Clara cells, ductal/glandular epithelia of various organs, myoepithelial cells, and non-epithelial cells such as macrophages, plasma cells, and part of the endothelial cells and fibroblasts. DPD was strongly expressed in adenocarcinomas of the lung, gallbladder and pancreas, hepatocellular carcinomas, and transitional cell carcinomas of the urinary bladder. Squamous cell carcinomas of the pharynx and lung were moderately reactive. Carcinomas of the breast and stomach revealed less consistent and less intense reactivity. Colorectal adenocarcinomas were not immunoreactive. The polyclonal antibody gave a broader and stronger reactivity than the monoclonal antibody KM1915, particularly in the normal epidermis and skin appendage as well as in squamous cell carcinomas and gastric cancers. The present results hopefully contribute to further investigations, in which the immunohistochemical demonstration of DPD is utilized as a tool of tailor-made chemotherapy for selecting of patients with cancer resistant to 5-FU and its derivatives.