Upregulation of thymidine phosphorylase in rectal cancer tissues by mitomycin C.
OBJECTIVE
We have investigated the regulation by mitomycin C (MMC) of thymidine phosphorylase (dThdPase) and dihydropyrimidine dehydrogenase (DPD), which enhances or reduces the efficacy of capecitabine and its metabolite 5'-deoxy-5-fluorouridine (5'-DFUR), in rectal cancer tissues.


METHODS
In 31 patients with a rectal cancer, tumor biopsies were performed before and after pre-operative venous administration of 4 mg/m2, 6 mg/m2, or 10 mg/m2 of MMC. The dThdPase and DPD levels in the biopsy and surgical specimens were measured using ELISA, and immunostaining for dThdPase was performed.


RESULTS
The fitting multiple linear regression models indicated that the dThdPase levels increased after MMC administration, in particular in the patients with a pre-treatment dThdPase level less than 56.2 U/mg protein (median value). The time course analysis indicated that the increase in the dThdPase level by 4 mg/m2 of MMC administration continued for 3 weeks. The dThdPase/DPD ratio was increased after MMC administration in patients with a pre-treatment dThdPase/DPD ratio less than 1.79 (median value). MMC enhanced the expression of dThdPase protein both in the tumor cells and in the stromal cells. The disease free-survival rate in the Dukes B or C patients with a high dThdPase/DPD ratio in surgical specimen who received 5'-DFUR based adjuvant chemotherapy tended to be higher than that in those with a low dThdPase/DPD ratio.


CONCLUSIONS
MMC may upregulate the dThdPase level and the dThdPase/DPD ratio in rectal cancer tissues. Combined use of MMC with capecitabine or 5'-DFUR may offer a more effective colorectal cancer therapy.
Ogata
Yutaka
Y
Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan. yogata@med.kurume-u.ac.jp
Matono
Keiko
K
Sasatomi
Teruo
T
Ishibashi
Nobuya
N
Torigoe
Shojiro
S
Fukumitsu
Takamasa
T
Mizobe
Tomoaki
T
Yamashita
Natsumi
N
Yanagawa
Takashi
T
Shirouzu
Kazuo
K
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000494:pharmacology; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology*; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000601:surgery; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D005467:Floxuridine; D003841:Deoxycytidine; D016685:Mitomycin; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine