Novel derivatives of 5-fluorouridine and 5-fluorouracil having potent antitumor and lower immunosuppressive activities.

Abstract

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.

• Authors: H Mori, O Sakamoto, K Kitaichi, A Koda, J Kita
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 58 Issue 3 Pg. 269-82 (Mar 1992) ISSN: 0021-5198 [Print] Japan
• PMID: 1513076 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Immunosuppressive Agents
• RNA, Ribosomal
• 5-fluorouridine
• Fluorouracil
• Uridine

Topics

• Animals
• Antibody Formation (drug effects)
• Antineoplastic Agents (pharmacology)
• Cell Division (drug effects)
• Fluorouracil (analogs & derivatives, pharmacology)
• Immunosuppressive Agents (pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Organ Size (drug effects)
• RNA, Ribosomal (antagonists & inhibitors)
• Thymus Gland (drug effects)
• Tumor Cells, Cultured (drug effects)
• Uridine (analogs & derivatives, pharmacology)