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Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889
Author(s) -
Endo Mika,
Miwa Masanori,
Eda Hiroyuki,
Ura Masako,
Tanimura Hiromi,
Ishikawa Tohru,
MiyazakiNose Taeko,
Hattori Kazuo,
Shimma Nobuo,
YamadaOkabe Hisafumi,
Ishitsuka Hideo
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11276
Subject(s) - capecitabine , dihydropyrimidine dehydrogenase , colorectal cancer , transfection , cancer research , cancer , fluorouracil , chemistry , pharmacology , medicine , biochemistry , gene , thymidylate synthase
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. © 2003 Wiley‐Liss, Inc.