Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889.

Article Details

Citation

Copy to clipboard

Endo M, Miwa M, Eda H, Ura M, Tanimura H, Ishikawa T, Miyazaki-Nose T, Hattori K, Shimma N, Yamada-Okabe H, Ishitsuka H

Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889.

Int J Cancer. 2003 Sep 20;106(5):799-805.

PubMed ID

12866042 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Capecitabine	Cytidine deaminase	Protein	Humans	No	Substrate	Details
Capecitabine	Liver carboxylesterase 1	Protein	Humans	No	Substrate	Details
Capecitabine	Thymidine phosphorylase	Protein	Humans	No	Substrate	Details