Comparative studies on the antitumor and immunosuppressive effects of the new fluorouracil derivative N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and its parent drug 5'-deoxy-5-fluorouridine.
N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a new prodrug of 5'-deoxy-5-fluorouridine (5'-dFUrd), was synthesized for the purpose of finding a drug with less intestinal toxicity than the parent compound. The present study compared the antitumor activity and immunotoxicity of Ro 09-1390 with those of 5'-dFUrd, 5-fluorouracil (5-FUra) and tegafur in various transplantable tumor models. The antitumor efficacy of Ro 09-1390 was comparable to 5'-dFUrd and these two agents were much more effective than the others. However, Ro 09-1390 was much less toxic to the intestinal tract and less immunosuppressive in both humoral and cellular immune reactions than 5'-dFUrd. Consequently, Ro 09-1390 showed higher therapeutic indices and higher efficacy than 5'-dFUrd at high dosages. The antitumor spectrum of Ro 09-1390 was somewhat different from that of 5'-dFUrd, though it shows the efficacy after it converts to 5'-dFUrd. The activity of Ro 09-1390 was partly associated with cytidine deaminase in the tumors treated. Ro 09-1390 appeared to be more effective against tumors with a high concentration of the enzyme by which the major metabolite 5'-deoxy-5-fluorocytidine (5'-dFCyd) is metabolized to 5'-dFUrd.
Miwa
M
M
Nippon Roche Research Center, Kanagawa, Japan.
Ishikawa
T
T
Eda
H
H
Ryu
M
M
Fujimoto
K
K
Ninomiya
Y
Y
Umeda
I
I
Yokose
K
K
Ishitsuka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D005467:Floxuridine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011355:Prodrugs; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011355:Prodrugs; D005467:Floxuridine; D003841:Deoxycytidine; C063993:Ro 09-1390; C025034:doxifluridine