Comparative antitumor activity and intestinal toxicity of 5'-deoxy-5-fluorouridine and its prodrug trimethoxybenzoyl-5'-deoxy-5-fluorocytidine.
N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a prodrug of the cytostatic 5'-deoxy-5-fluorouridine (5'-DFUR), was synthesized with the aim of reducing of the dose-limiting toxicity of 5'-DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5'-DFUR given po produced a substantial amount of 5-fluorouracil (5-FU) in the intestinal tract as well as tumors, where the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5'-DFUR to 5-FU, is predominantly located. With the oral administration of Ro 09-1390 only a small amount of 5-FU was formed in the intestine; however, the administration of Ro 09-1390 and 5'-DFUR at the same dose produced similar amounts of 5-FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5'-DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09-1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09-1390 and 5'-DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09-1390 was much less toxic to the intestinal tract than 5'-DFUR, mice bearing Lewis lung carcinoma could be given Ro 09-1390 daily over a longer period and at a higher dose, resulting in a longer survival time.
Ninomiya
Y
Y
Nippon Roche Research Center, Kanagawa.
Miwa
M
M
Eda
H
H
Sahara
H
H
Fujimoto
K
K
Ishida
M
M
Umeda
I
I
Yokose
K
K
Ishitsuka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011355:Prodrugs / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D011355:Prodrugs; D005467:Floxuridine; D003841:Deoxycytidine; C063993:Ro 09-1390; D005472:Fluorouracil; C025034:doxifluridine