The significance of the expression of dihydropyrimidine dehydrogenase in prostate cancer.
OBJECTIVE
To measure dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of 5-fluorouracil (5-FU), expression in prostate cancer and determine whether 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of DPD, enhances the antitumoral activity of 5-FU against prostate cancer.


METHODS
In all, 44 prostate tissue specimens were obtained from men who had a radical prostatectomy alone for prostate cancer, and 38 specimens from men who had had neoadjuvant hormonal therapy. We analysed the cancerous tissue and normal prostate tissue for DPD expression using immunohistochemistry, and determined its prognostic significance. In cultured human prostate cancer lines (DU145 and LNCaP), we compared the cytotoxicity of 5-FU/CDHP with that of 5-FU alone. Finally, in experiments on immunodeficient mice, we studied the effect of oral administration of tegafur, a pro-drug for 5-FU, with or without CDHP on the growth of tumours introduced by injection of DU145 cells.


RESULTS
The expression of DPD was significantly higher in cancerous than normal prostate tissue; 36 of 44 (82%) specimens of prostate cancer expressed DPD, whereas only 25 of 44 (57%) specimens of normal prostate tissue expressed DPD. For men with prostate cancer who had radical prostatectomy alone, men with negative DPD expression tended to have a longer recurrence-free survival than those with positive expression; there were no recurrences in men with prostate cancer and negative DPD expression in the 5-year follow-up. DPD expression was significantly lower in men with prostate cancer who received neoadjuvant hormonal therapy. In vitro treatment of human prostate cancer cell lines with 5-FU/CDHP showed more cytotoxicity than with 5-FU treatment alone. Finally, DU145 tumours in mice treated with tegafur and CDHP were significantly smaller than in mice given tegafur alone.


CONCLUSIONS
The present study showed that DPD expression is elevated in prostate cancer, and indicate that DPD inhibitors might enhance the antitumour activity of 5-FU against prostate cancer.
Li
Yongnan
Y
Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Mizutani
Yoichi
Y
Shiraishi
Takumi
T
Nakamura
Terukazu
T
Mikami
Kazuya
K
Takaha
Natsuki
N
Okihara
Koji
K
Kawauchi
Akihiro
A
Sakai
Toshiyuki
T
Miki
Tsuneharu
T
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017024:Chemotherapy, Adjuvant; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D011725:Pyridines; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; C104201:gimeracil