Capecitabine is an orally available fluoropyrimidine and is finally converted to
5-FU selectively in
tumor tissues. In our study, we examined whether the antitumor activity of
capecitabine is directly affected by a modulation of
dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in
tumor cells and by
tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD
cDNA into HCT116 human
colorectal cancer cells. The HCT116 cells bearing DPD
cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to
capecitabine than the parental cells when transplanted into nude mice. Administration of
RO0094889 that is converted to a DPD inhibitor
5-vinyluracil selectively in
tumor tissues restored the antitumor activity of
capecitabine against the
tumor of the HCT116 cells carrying DPD
cDNA and various
tumors expressing DPD. As compared to
5-ethynyluracil or
5-vinyluracil, which inhibited DPD not only in
tumor tissues but also in other non-cancerous tissues, the effective dose range of
RO0094889 in augmenting the efficacy of
capecitabine was much broader. These results indicate that the antitumor activity of
capecitabine is directly affected by DPD activities in
tumor tissues and therefore, the combination of
capecitabine and a
tumor selective DPD inhibitor,
RO0094889, will be beneficial to patients who have
tumors with high levels of DPD.