In situ transduction of cytosine deaminase gene followed by systemic use of 5-fluorocytosine inhibits tumor growth and metastasis in orthotopic prostate cancer mouse models.
OBJECTIVE
To investigate the antitumor and anti-metastatic effect of in situ transduction of adenovirus encoding cytosine deaminase (AdCD) followed by the systemic use of 5-fluorocytosine (5-FC) in the orthotopic (o.t.) prostate cancer mouse model.


METHODS
The o.t. prostate cancer model of C57BL/6 mouse was developed by o.t. inoculation of RM-1 cells to the subcapsular area of the prostate gland. In situ transduction of the CD gene, followed by systemic use of 5-FC at a daily dosage of 300 mg/kg for 14 days, was performed two days later.


RESULTS
Compared with mice treated with Adbeta-gal/5-FC, 5-FC and PBS, mice of the o.t. model receiving in situ treatment of AdCD/5-FC had significant prolongation of survival and suppression of local tumor growth. More importantly, pathological observations showed that metastatic activity occurred in all mice of the PBS, 5-FC and Adbeta-gal groups including metastasis to the iliac lymph node (10/10, 10/10, 10/10) and the lung (8/10, 7/10, 7/10). However, only two out of ten had iliac lymphatic metastasis in the AdCD/5-FC group with no systemic or preaotic lymphatic metastasis, suggesting a strong metastatic inhibitory effect.


CONCLUSIONS
In situ transduction of AdCD followed by systemic use of 5-FC leads to the inhibitory effect on tumor growth and metastatic activity in the o.t. mouse model of prostate cancer. Clinically, it may be possible to treat metastatic or recurrent prostate cancer with a novel gene therapy using in situ injection techniques in future.
Zhang
Zhengwang
Z
Department of Urology, Zhongshan Hospital, Shanghai 200032, China.
Yin
Lianhua
L
Zhang
Yongkang
Y
Zhao
Fengdi
F
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D043525:Cytosine Deaminase; D004195:Disease Models, Animal; D005437:Flucytosine / Q000494:pharmacology*; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured
D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase