Effect of administration of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on the anti-tumor efficacy of 5-fluoro-2′-deoxyuridine against murine colon tumor C26–10

doi:10.1016/S0006-2952(00)00375-0

Biochemical Pharmacology

Volume 60, Issue 5, 1 September 2000, Pages 687-692

https://doi.org/10.1016/S0006-2952(00)00375-0 Get rights and content

Abstract

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 μmol/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.

Section snippets

Chemicals

[2-¹⁴C]Uridine (56 Ci/mol), [2-¹⁴C]thymidine (56 Ci/mol), [2-¹⁴C]FdUrd (56 Ci/mol), [6-¹⁴C]uracil (55 Ci/mol), and [2-¹⁴C]orotic acid (55 Ci/mol) were purchased from Moravek Biochemicals, Inc. Silica gel G/UV₂₅₄ TLC polygram plates were obtained from Fisher Scientific. CEL 300/UV₂₅₄ cellulose and 300 PEI/UV₂₅₄ polyethyleneimine–cellulose polygram TLC plates were from Brinkmann Instruments, Inc. Bovine γ-globulin and dye reagent for protein assays were from Bio-Rad Laboratories. PSAU was

Results

The results in Table 1show that PSAU alone at 15, 25, and 50 mg/kg × 5 days produced no toxicity or mortality in mice. Similarly, at 60 mg/kg/day × 2/week × 3, PSAU had no toxic effect on the growth of colon C26–10 tumor in vivo(Table 2).

Table 2 shows the results of administering different doses of FdUrd alone and in combination with PSAU (60 mg/kg/day × 2/week × 3). Administration of FdUrd alone at doses of 100, 200, and 300 mg/kg/day × 2/week × 3 produced a significant reduction in tumor

Discussion

In contrast to our previous results with human tumors 15, 18, the present study demonstrates that co-administration of a UrdPase inhibitor (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 from the 83% mortality induced by the same dose of FdUrd alone (Table 2). The failure of PSAU to potentiate FdUrd antitumor efficacy in colon C26–10 tumor could be explained on the

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Chemotherapy and metabolic inhibitorsEffect of administration of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on the anti-tumor efficacy of 5-fluoro-2′-deoxyuridine against murine colon tumor C26–10

Abstract

Section snippets

Chemicals

Results

Discussion

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Lancet

Leuk Res

Biochem Pharmacol

Biochem Pharmacol

Bioorg Med Chem Lett

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Int J Parasitol

Anal Biochem

Differences in activities and substrate specificity of human and murine pyrimidine nucleoside phosphorylasesImplication for chemotherapy with 5-fluoropyrimidines

Cancer Res

Thymidine catabolism by normal and leukemic human leukocytes

J Clin Invest

Divergent properties of two human lymphocytic cell lines isolated from a single specimen of peripheral blood

In Vitro

Chemotherapy and metabolic inhibitors
Effect of administration of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on the anti-tumor efficacy of 5-fluoro-2′-deoxyuridine against murine colon tumor C26–10