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The effect of co-administration of 5-(phenylselenenyl)acyclouridine (PSAU), a new uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on the efficacy of 5-fluoro-2'-deoxyuridine (FdUrd) was tested against murine colon C26-10 tumor xenografts. In contrast to our previous results with human tumors, co-administration of PSAU with FdUrd decreased instead of increasing the efficacy of FdUrd against tumor growth. However, co-administration of PSAU with FdUrd (300 mg/kg/day) protected the mice completely from the 83% mortality induced by the same dose of FdUrd alone. Enzyme studies indicated that UrdPase in colon C26-10 tumors is responsible for the catabolism of FdUrd to 5-fluorouracil (FUra), as colon C26-10 tumors do not have thymidine phosphorylase (dThdPase, EC 2.4.2.4). In contrast, colon C26-10 tumors had extraordinarily high UrdPase activity (300 micromol/min/mg protein), which was at least 200-fold higher than the highest UrdPase activity in any of the human xenografts we tested previously. Furthermore, the activities of UrdPase and orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) were 192- and 2-fold higher, respectively, while that of dihydrouracil dehydrogenase (EC 1.3.1.2) was 1000-fold lower in the tumor than in the host liver. It is suggested that FdUrd exerts its anticancer effects against colon C26-10 tumors mainly through the catabolism of FdUrd to FUra by UrdPase, which then could be anabolized to 5-fluorouridine 5'-monophosphate (FUMP) by OPRTase and ultimately to other toxic 5-fluorouridine nucleotides, hence inducing the observed FdUrd toxic effects. Co-administration of PSAU with FdUrd inhibited UrdPase and the catabolism of FdUrd to FUra. This would result in the observed reduction of the antitumor efficacy of FdUrd. In addition, the increase in plasma uridine concentration induced by PSAU as well as the catabolism of FUra by the high dihydrouracil dehydrogenase activity in the liver also may have circumvented any residual FUra toxic effects against the host. These results clearly demonstrate that the anticancer efficacy of the combination of UrdPase inhibitors and FdUrd is not general and is dependent largely on the type of tumor under treatment and the mode of FdUrd metabolism in these tumors.

Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2',3',5'-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself., Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed., Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 micromol x h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil., Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.

Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU is a new potent and specific inhibitor of uridine phosphorylase (Urd-Pase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism., Methods: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed., Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 +/- 0.7 microM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (C(max)) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1,320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1,421 to 787 micromol/h x l and 273 micromol/h x l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1,320 mg/kg uridine was used., Conclusion: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.

Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy.