Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889.
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.
Endo
Mika
M
Department of Oncology, Nippon Roche Research Center, Kajiwara, Kamakura, Kanagawa, Japan.
Miwa
Masanori
M
Eda
Hiroyuki
H
Ura
Masako
M
Tanimura
Hiromi
H
Ishikawa
Tohru
T
Miyazaki-Nose
Taeko
T
Hattori
Kazuo
K
Shimma
Nobuo
N
Yamada-Okabe
Hisafumi
H
Ishitsuka
Hideo
H
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D000069287:Capecitabine; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
C477084:2',3'-O-diacetyl-5'-deoxy-5-vinylcytidine; D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D000069287:Capecitabine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil