5-Fluorouracil is converted to F-nucleotides more extensively and is more cytotoxic in poorly differentiated than in well differentiated human gastric carcinoma

The sensitivity to 5-flourouracil (5-FU) was examined in 40 well differentiated and 50 poorly differentiated gastric cancer tissues and 15 normal tissues, using the in vitro succinate dehydrogenase inhibition (SDI) test. The tissue phosphorylating and degrading activities of 5-FU were compared in each type of tumor and in the normal tissues. Decreases in succinate dehydrogenase (SD) activity were more apparent in the poorly differentiated cancer tissues than in the well differentiated cancer tissues (p < 0.005), and than in the normal tissues (p < 0.001), exposed to 5-FU. The rate of sensitivity to 5-FU was higher in the poorly differentiated than in the well differentiated tissues and than in the normal tissues. The phosphorylating activities of 5-FU, in pathways involving uridine (Urd) phosphorylase and Urd Kinase, and thymidine (dThd) phosphorylase and dThd Kinase, were 1.7 fold higher in the poorly differentiated than in the well differentiated tissues and several fold higher than in the normal tissues (p < 0.05-p < 0.001). The degrading activity of 5-FU was similar in both types of tumor and in the normal tissues. Our findings show that 5-FU is actively metabolized to 5-FU-nucleotides in poorly differentiated tissues after incorporation into the tumor cells. 5-FU seems to have an increased susceptibility in cases of poorly differentiated gastric carcinoma.