Combination of oral fluoropyrimidine and docetaxel: reappraisal of synergistic effect against gastric carcinoma xenografts.
BACKGROUND
The synergistic antitumor effect of a combination of docetaxel and capecitabine is reported to be attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (dThdPase).


METHODS
Intravenous docetaxel (15 mg/kg) was given to nude mice bearing xenografts of the gastric cancer cell lines MKN45 and MKN28. Mice were sacrificed on days 7, 10 and 22 and tumor samples were taken to measure the activities of thymidylate synthase, dihydropyrimidine dehydrogenase, dThdPase and orotate phosphoribosyltransferase. The efficacy of capecitabine or S-1, alone and in combination with docetaxel, was then evaluated in vivo. Docetaxel was administered intravenously on days 8 and 22 at 15 mg/kg, while capecitabine (269 mg/kg) or S-1 (7.5 mg/kg) were administered orally 5 times a week for 4 weeks.


RESULTS
Tumor regression was observed only for a combination of capecitabine and docetaxel against MKN28, while additive growth inhibition was obtained by the combination of docetaxel and both S-1 and capecitabine on MKN45 tumor xenografts. Induction of dThdPase activity was observed only for MKN45. The activity of no other enzyme was significantly affected following administration of docetaxel.


CONCLUSIONS
The combination of oral fluoropyrimidine and docetaxel showed augmented antitumor activity, but this may be attributed to mechanisms other than changes in 5-fluorouracil-metabolizing enzymes.
Kodera
Yasuhiro
Y
Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. ykodera@med.nagoya-u.ac.jp
Fujiwara
Michitaka
M
Yokoyama
Hiroyuki
H
Ohashi
Norifumi
N
Miura
Shinichi
S
Ito
Yuichi
Y
Koike
Masahiko
M
Ito
Katsuki
K
Nakao
Akimasa
A
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D000077143:Docetaxel; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D009962:Orotate Phosphoribosyltransferase / Q000096:biosynthesis; D011743:Pyrimidines / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis / Q000378:metabolism; D013940:Thymidylate Synthase / Q000096:biosynthesis; D013997:Time Factors; D015854:Up-Regulation
D000970:Antineoplastic Agents; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; C029269:5-fluoropyrimidine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase