Overexpression of orotate phosphoribosyl transferase in hormone-refractory prostate cancer.
Orotate phosphoribosyl transferase (OPRT) is the initial enzyme of 5-fluorouracil (5-FU) activation, in which 5-FU is converted to 5-fluorouridinemonophosphate. Dihydropyrimidine dehydrogenase (DPD) is a degrading enzyme that catabolizes 5-FU. In this study, we investigated the expression of these enzymes in normal prostate gland (NP), hormone-sensitive prostate cancer (HSPC) and hormone-refractory prostate cancer (HRPC). Forty-two prostatic tissue specimens were obtained from patients who had undergone prostate needle biopsies without any treatments or with PSA failure after initial androgen deprivation. The tissue samples derived from formalin-fixed, paraffin-embedded sections were made by laser-captured microdissection and from those RNA was extracted. The levels of OPRT and DPD mRNA expression were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The level of OPRT mRNA expression in the HSPC or the HRPC specimens was significantly higher than that in the NP specimens. Immunohistochemical staining for OPRT revealed strong expression of OPRT in prostate cancer cells. There was a significant correlation between OPRT mRNA expression levels and the tumor pathological grade. Furthermore, the OPRT/DPD expression ratio, a powerful predictive factor to evaluate 5-FU sensitivity, in the HRPC group was significantly higher than that in the low grade HSPC group. Thus, 5-FU may be an effective option for some HRPC patients.
Tanaka
Tomoaki
T
Department of Urology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. tomoaki826@msic.med.osaka-cu.ac.jp
Kawashima
Hidenori
H
Matsumura
Kentaro
K
Yamashita-Hosono
Tomoko
T
Yoshimura
Rikio
R
Kuratsukuri
Katsuyuki
K
Harimoto
Koji
K
Nakatani
Tatsuya
T
D000970:Antineoplastic Agents / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D042282:Microdissection; D009962:Orotate Phosphoribosyltransferase / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil