Novel low immunosuppressive derivatives of the antitumor drug fluoropyrimidine, UK-21 and UK-25: effect on delayed type hypersensitivity and tumor immunity.

Previously, we reported that two novel 5-fluoropyrimidine derivatives, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21) and 1-(6-[N-(2-n-propyl-n-pentanoyl)glycyl]amino-n-hexylcarbamoyl)- 5-fluorouracil (UK-25), show potent antitumor activity with low immunotoxicological effects. The purpose of this paper was to evaluate the effect of these drugs on delayed type hypersensitivity (DTH). Not only UK-21 and UK-25 but also tegafur (FT-207) and 5-fluorouracil (5-FU) produced no suppression of picryl chloride (PC)-induced DTH in mice but rather enhanced it. It is known that variation of the sensitizing antigen dose alters the effect of drugs on the immune response. Because it was difficult to control the antigen dose in PC-DTH, the sheep erythrocyte (SRBC)-induced response was used to examine the effect of drugs on delayed type hypersensitivity in the succeeding experiments. Either a therapeutic dose or an over-dose of the respective drug was given to mice sensitized with 5 x 10(5) or 5 x 10(7) SRBC. The suppressive effects of UK-21 and UK-25 on the DTH were lower than those of FT-207 and 5-FU. UK-21 and UK-25 enhanced Meth A tumor-specific DTH in BALB/c mice, but FT-207 and 5-FU did not. UK-21, UK-25 and FT-207 showed a tendency to enhance or restore the Meth A tumor neutralizing activity of spleen cells in mice bearing the tumor, but carmofur (HCFU) did not. These results indicated that the suppressive effects of UK-21 and UK-25 on the tumor immune response were also low.