Tezacitabine is a
nucleoside analogue characterized by a dual mechanism of action. Following intracellular phosphorylation, the
tezacitabine diphosphate irreversibly inhibits
ribonucleotide reductase, while the
tezacitabine triphosphate can be incorporated into
DNA during replication or repair, resulting in
DNA chain termination. In the present study we have investigated the effect of the combination of
tezacitabine and
5-fluorouracil (5-FU) or
5-fluoro-2'-deoxyuridine (
FUdR) on HCT 116 human colon
carcinoma cells and xenografts. We used response surface analysis (RSA) and clonogenic assay to evaluate combination effects of
tezacitabine and
5-FU.
Tezacitabine is antagonistic when combined with
5-FU in the RSA assay and does not effect the clonogenicity of HCT 116 cells when compared with cells treated with
5-FU alone. However, when combined sequentially with
FUdR,
tezacitabine leads to potentiation of cell killing in the clonogenic assay, additivity in the RSA assay, and increased apoptosis when compared to
FUdR alone, suggesting that cytotoxicity of fluoropyrimidines such as
FUdR that have more
DNA-directed effects can be potentiated by
tezacitabine. We also report that
oral administration of the fluoropyrimidine
capecitabine, an oral
prodrug of
5-FU, in combination with
tezacitabine shows statistically significant additivity in the HCT 116 xenograft model. This interaction may be explained by the finding that
tezacitabine elevates activity of
thymidine phosphorylase (TP), the
enzyme required for activation of the
capecitabine prodrug in
tumors. Our results provide evidence that
tezacitabine enhances the
DNA-directed effects of fluoropyrimidines in human
colon cancer cells and may modulate the antitumor activity of fluoropyrimidines.