Novel derivatives of 5-fluorouridine and 5-fluorouracil having potent antitumor and lower immunosuppressive activities.
We studied the biological activities of several 5-fluorouridine (5-FUR) and 5-fluorouracil (5-FU) derivatives to find novel antitumor drugs with lower immunosuppressive effects. We examined 5-FUR and 5-FU derivatives acylated with (2-n-propyl-n-pentanoyl)glycine (KN-539). Among the examined compounds, we found satisfactory activities in a derivative of 5-FUR, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), and a derivative of 5-FU, 1-(6-[N-(2-n-propyl-n-pentanoyl)glycyl] amino-n-hexylcarbamoyl)-5-fluorouracil (UK-25). UK-21 (0.05-0.2 mmole/kg, p.o., 10 days) and UK-25 (0.1-0.4 mmole/kg, p.o., 10 days) suppressed Meth A and E.L.4 tumor growths in the corresponding syngeneic hosts (BALB/c mice and C57BL/6 mice, respectively) without decreasing body weight and blood leukocyte count. UK-21 and UK-25 suppressed the proliferation of KB tumor cells in vitro (IC50: 3.0 x 10(-11) M and 4.4 x 10(-7) M, respectively) at concentrations almost equivalent to those of 5-FUR and 5-FU, respectively. These results suggest that UK-21 and UK-25 express their antitumor activity as 5-FUR and 5-FU, respectively. Neither UK-21 nor UK-25 suppressed thymus weight and humoral antibody production against sheep red blood cells (SRBC) in ddY mice, although 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-FU suppressed them in their respective therapeutic dose ranges for tumors. Thus, UK-21 and UK-25 are expected to develop into anticancer drugs with lower immunotoxicological effects.
Mori
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Sakamoto
O
O
Kitaichi
K
K
Koda
A
A
Kita
J
J
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors*; D013950:Thymus Gland / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D012335:RNA, Ribosomal; C001943:5-fluorouridine; D005472:Fluorouracil; D014529:Uridine