Experimental studies on potentiation of the antitumor activity of 5-fluorouracil with 3'-azido-3'-deoxythymidine for the gastric cancer cell line MKN28 in vivo

Abstract

A new method of biochemical modulation of 5-fluorouracil (5-FU) with 3'-azido-3'-deoxythymidine (AZT) was studied experimentally. Nude mice transplanted with cells of the human gastric cancer cell line MKN28 were divided into 4 groups, i.e., control, 5-FU, AZT, and 5-FU plus AZT, and the antitumor activities were compared. Based on the assessment of tumor volume, significant suppression of tumor growth was observed in the 5-FU and 5-FU plus AZT groups (P<0.05, P<0.01, versus control, respectively). The thymidylate synthase (TS) inhibition rate, an index of inhibition of the de novo pathway, was significantly higher in the 5-FU and 5-FU plus AZT groups than in the control group (P<0.01), but it did not differ from the control in the AZT group. TS-bound FdUMP tended to be higher in the 5-FU plus AZT group than in the 5-FU group. The activity of thymidine kinase (TK) and the uptake ratio of 5-bromo-2'-deoxyuridine (BrdU), indices of salvage pathway activity, were significantly lower in the AZT and 5-FU plus AZT groups than in the control group (TK, P< 0.05, P < 0.01; uptake ratio of BrdU, P < 0.01, P < 0.05, respectively). There were slight losses of body weight in the 5-FU and 5-FU plus AZT groups compared with that in the control group, but no difference between the AZT and control groups in weight loss. These findings suggest that addition of AZT plays an important role in potentiating the antitumor activity of 5-FU through both blockage of a compensatory increase of activity in the salvage pathway and also an increase in TS-bound FdUMP, and has no adverse effects. Thus, the combination of 5-FU and AZT could be useful as a new modality in gastric cancer chemotherapy.