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-fluorouridine derivative, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), revealed its antitumor activity by being converted to 5-fluorouridine (5-FUR) and showed a low level of immunological side effects. However, the bioavailability of UK-21 given orally did not 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 suppressed the growth of L-1210, P388 and EL4 leukemias inoculated i.v. into corresponding syngeneic mice and both the growth of Lewis lung carcinoma transplanted s.c. and its subsequent metastasis to the lung. UK-21 showed antitumor activity at doses almost 10 times lower than those 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-FU, and cyclophosphamide (CY) at doses producing comparable antitumor activity. The suppressive effect of UK-21 on IgM and IgG antibody formation 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 counts induced by UK-21 was also lower than that produced by any other agent. The results reported herein suggest the strong possibility of UK-21 being developed as a novel anticancer drug with cytotoxic mechanisms 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 drugs.
Mori
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Nakayama
K
K
Maeda
D
D
Nagai
H
H
Koda
A
A
Kita
J
J
Kaku
Y
Y
D000704:Analysis of Variance; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014529:Uridine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; C078136:UK 21; D005998:Glycine; D014529:Uridine