Comparative Antitumor Activity and Intestinal Toxicity of 5′‐Deoxy‐5‐fluorouridine and Its Prodrug Trimethoxybenzoyl‐5′‐deoxy‐5‐fluorocytidine

Abstract

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.

Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:19F NMR Studies in Animal Models and Human Urine

“…Therefore, CAP activation appears to be blocked at the cytidine deaminase step. This confirms the low cytidine deaminase activity in rat liver (Camenier and Smith, 1965) and suggests a lack of an extra-hepatic cytidine deaminase activity in rat in agreement with previous studies on other 5Ј-DFCR-related compounds such as galocitabine (Ninomiya et al, 1990;Funaki et al, 1993). On the contrary, the high activity of cytidine deaminase is revealed by the low value of the 5Ј-DFCR/5Ј-DFUR ratio (Ͻ1) in mice treated with a LD or a HD of CAP.…”

“…Since cholestasis has not been described as a side effect of CAP treatment, it is likely that 5Ј-DFCR-G does not affect the physicochemical properties of bile in contrast to what has been observed with a biliary conjugate of FBAL (Sweeny et al, 1987). The third activation step of CAP leads to the formation of 5-FU that occurs mainly via uridine phosphorylase in rodents and thymidine phosphorylase in humans (Ninomiya et al, 1990). FBAL, the main catabolite of 5-FU, is formed since dihydropyrimidine dehydrogenase (E.C.…”

Bioactivation of Capecitabine in Human Liver: Involvement of the Cytosolic Enzyme on 5′-Deoxy-5-Fluorocytidine Formation

“…Oral administration requires higher dosages than intravenous injection due to first pass effects. Adverse effects such as diarrhea have been reported following the administration of tegafur or doxifluridine (Ohta et al, 1980;Ninomiya et al, 1990).…”

RELATIONSHIP BETWEEN AUC of 5'-DFUR AND TOXICITY OF CAPECITABINE, FLUOROPYRIMIDINE CARBAMATE ANALOGS, AND 5'-DFUR IN MONKEYS, MICE, AND RATS

“…When galocitabine was given orally to mice, only a small amount of 5-FU was formed in the intestine. On the other hand, when 5'-DFUR was given orally to mice, a substantial amount of 5-FU was produced in the intestine and more severe intestinal toxicity was observed compared with that of galocitabine (Ninomiya et al, 1990). These results suggested that oral 5'-DFUR could be converted to 5-FU at the absorption site by TP; however, galocitabine produced less 5-FU during the absorption process.…”

“…Before the development of capecitabine, galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), an acyl-type analog, had been selected as the new fluoropyrimidine candidate (Ninomiya et al, 1990). While it was effectively converted to 5'-DFCR by hepatic enzymes in mice, it was not converted so effectively by hepatic CE in humans.…”