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
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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