TY - JOUR
T1 - Enhancement of 5-Fluoro-2'-deoxyuridine Antineoplastic Activity by 5-Benzyloxybenzyloxybenzylacyclouridine in a Human Colon Carcinoma Cell Line
AU - Chu, Edward
AU - Chu, Ming Y.
AU - Darnowski, James W.
AU - Chen, Zhi H.
AU - Pan, Bai C.
AU - Chu, Shih H.
PY - 1992/4
Y1 - 1992/4
N2 - The pyrimidine acyclonncleoside benzyloxybenzyloxybenzylacyclonri-dine (BBBAU) showed growth inhibitory activity against the human colon cancer HCT-8 ceU line with a 50% inhibitory concentration of 55 MM. Unlike its parent compounds, BBBAU was an extremely weak inhibitor of uridine phosphorylase. This acyclonucleoside analogue is an inhibitor of thymidylate synthase (TS) as determined by inhibition of |6-3H]-2'-deoxyuridine incorporation into DNA, inhibition of 3H release from [5-3HJ-2'-deoxyuridine, and decrease in both the free and total TS 5' -fluoro-2' -deoxyuridine 5' -monophosphate binding sites. Kinetic analysis revealed that BBBAUMP, the monophosphate analogue of BBBAU, is a competitive inhibitor of purified human recombinant TS with a K\ of 8.0 MM. Nucleoside transport and uptake studies revealed that BBBAU (10 MM) inhibited the initial rate of transport and the total uptake of thymidine (25 MM). In contrast, while BBBAU (30 MM) inhibited the initial rate of transport of 5-fluoro-2'-deoxyuridine (FdUrd, 25 MM), its intracellular accumulation was increased. BBBAU (10 and 50 MM, respectively) potentiated FdUrd growth inhibition of HCT-8 cells and significantly enhanced the cytotoxic effects of FdUrd (03 and 1 MM, respectively) against HCT-8 cells using a clonogenic assay system. This combination resulted in additive inhibitory effects on TS activity resulting in greater depletion of dTTP pools. Moreover, the incorporation of radiolabeled FdUrd into the DNA fraction of HCT-8 cells was enhanced. The potential importance of this novel combination for human colon cancer chemotherapy is discussed.
AB - The pyrimidine acyclonncleoside benzyloxybenzyloxybenzylacyclonri-dine (BBBAU) showed growth inhibitory activity against the human colon cancer HCT-8 ceU line with a 50% inhibitory concentration of 55 MM. Unlike its parent compounds, BBBAU was an extremely weak inhibitor of uridine phosphorylase. This acyclonucleoside analogue is an inhibitor of thymidylate synthase (TS) as determined by inhibition of |6-3H]-2'-deoxyuridine incorporation into DNA, inhibition of 3H release from [5-3HJ-2'-deoxyuridine, and decrease in both the free and total TS 5' -fluoro-2' -deoxyuridine 5' -monophosphate binding sites. Kinetic analysis revealed that BBBAUMP, the monophosphate analogue of BBBAU, is a competitive inhibitor of purified human recombinant TS with a K\ of 8.0 MM. Nucleoside transport and uptake studies revealed that BBBAU (10 MM) inhibited the initial rate of transport and the total uptake of thymidine (25 MM). In contrast, while BBBAU (30 MM) inhibited the initial rate of transport of 5-fluoro-2'-deoxyuridine (FdUrd, 25 MM), its intracellular accumulation was increased. BBBAU (10 and 50 MM, respectively) potentiated FdUrd growth inhibition of HCT-8 cells and significantly enhanced the cytotoxic effects of FdUrd (03 and 1 MM, respectively) against HCT-8 cells using a clonogenic assay system. This combination resulted in additive inhibitory effects on TS activity resulting in greater depletion of dTTP pools. Moreover, the incorporation of radiolabeled FdUrd into the DNA fraction of HCT-8 cells was enhanced. The potential importance of this novel combination for human colon cancer chemotherapy is discussed.
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M3 - Article
C2 - 1532344
AN - SCOPUS:0026684511
SN - 0008-5472
VL - 52
SP - 1729
EP - 1736
JO - Cancer research
JF - Cancer research
IS - 7
ER -
