Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system.
BACKGROUND
Cytosine deaminase (CD) activates prodrug 5-FC to 5-FU and is used for suicide gene therapy (the CD/5-FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5-FU into 5-fluorouridine monophosphate and improves the antitumoral effect of 5-FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5-FC cancer suicide gene therapy.


METHODS
We investigated a combined suicide gene transduction therapy for human hormone independent prostate cancer cell line DU145 using two separate adenovirus vectors expressing the E. coli CD and E. coli UPRT genes and systemic 5-FC administration (the CD+UPRT/5-FC system).


RESULTS
Cells transfected with AdCA-UPRT showed approximately 57 times lower IC50 to 5-FU compared with those transfected with AdCA-LacZ. Furthermore, cells transfected with AdCA-CD and AdCA-UPRT proved to be more sensitive to 5-FC compared with those transfected with AdCA-CD. Intratumoral injection of AdCA-CD and AdCA-UPRT drastically suppressed the growth of tumors which had generated from DU145 cells inoculated into athymic (nude) mice compared with those injected with AdCA-LacZ or AdCA-LacZ and AdCA-CD.


CONCLUSIONS
These results suggest that the CD+UPRT/5-FC system could be a powerful factor in human prostate cancer suicide gene therapy.
Miyagi
Tohru
T
Department of Urology, Kanazawa University School of Medicine, Kanazawa, Japan.
Koshida
Kiyoshi
K
Hori
Osamu
O
Konaka
Hiroyuki
H
Katoh
Hiroaki
H
Kitagawa
Yasuhide
Y
Mizokami
Atsushi
A
Egawa
Masayuki
M
Ogawa
Satoshi
S
Hamada
Hirohumi
H
Namiki
Mikio
M
D000256:Adenoviridae; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D043525:Cytosine Deaminase; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics*; D010430:Pentosyltransferases / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000628:therapy*
D000964:Antimetabolites, Antineoplastic; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil