NOVEL LOWLY IMMUNOSUPPRESSIVE ANTITUMOR FLUOROURIDINE DERIVATIVE, UK-21 - ANTITUMOR-ACTIVITY AND EFFECT ON HUMORAL IMMUNE-RESPONSE IN MICE

Our previous studies indicated that a newly synthesized 5-fluorouridin e derivative, 2',3',5'- tris-O-[N-(2-n-propyl-n-pentanoyl) glycyl]-5-f luorouridine (UK-21), revealed its antitumor activity by being convert ed to 5-fluorouridine (5-FUR) and showed a low level of immunological side effects. However, the bioavailability of UK-21 given orally did n ot seem to be good. In the present study, we focused on the antitumor and immunosuppressive activities of UK-21 given i.p. to mice. UK-21 su ppressed the growth of L-1210, P388 and EL4 leukemias inoculated i.v. into corresponding syngeneic mice and both the growth of Lewis lung ca rcinoma transplanted s.c. and its subsequent metastasis to the lung. U K-21 showed antitumor activity at doses almost 10 times lower than tho se of 5-fluorouracil (5-FU). The side effects of UK-21, especially on immune functions, were examined in comparison with those of 5-FUR, 5-F U, and cyclophosphamide (CY) at doses producing comparable antitumor a ctivity. The suppressive effect of UK-21 on IgM and IgG antibody forma tion in mice immunized with ovalbumin was clearly weaker than that of 5-FUR, 5-FU, and CY. The suppressive effect of UK-21 on thymus weight was markedly weaker than that of 5-FU and CY. The reduction of WBC cou nts induced by UK-21 was also lower than that produced by any other ag ent. The results reported herein suggest the strong possibility of UK- 21 being developed as a novel anticancer drug with cytotoxic mechanism s different from those of 5-FU. Our study also points to the chemical modification of 5-FUR as a feasible way of developing new anticancer d rugs.