Potential benefits of combining cytosine deaminase/5-fluorocytosine gene therapy and irradiation for prostate cancer: experimental study.
BACKGROUND
The purpose of this study was to investigate the potential of combining cytosine deaminase/5-fluorocytosine (CD/5-FC) gene therapy and radiation therapy (either external beam radiation or radioimmunotherapy [RIT]), for the treatment of prostate cancer.


METHODS
Tumor xenografts of CD-transduced LNCaP cells grown in the testes of severe combined immunodeficiency (SCID) mice were used to evaluate antitumor effect. The mice were injected intraperitoneally with 500 mg/kg of 5-FC, or with 5, 15 or 30 mg/kg of 5-fluorouracil (5-FU), for 9 days. The tumors were treated with fractionated radiation at a dose of 1 or 3 Gy/day for 3 days, or I-131 labelled anti-prostate specific antigen (anti-PSA) monoclonal antibody (mAb) administration at a subtherapeutic dose of 20 or 80 micro Ci. Intratumoral and serum concentrations of 5-FU were measured using high performance liquid chromatography.


RESULTS
Mice treated with CD/5-FC gene therapy presented a significant tumor growth inhibition comparable to that obtained with 15 mg/kg, 5-FU systemic administration without marked weight loss. Treatment with CD/5-FC gene therapy resulted in higher tumor but lower serum concentrations of 5-FU than treatment with systemic 5-FU chemotherapy. An additive antitumor effect was obtained when CD/5-FC therapy was combined with 1 Gy irradiation, which by itself did not produce a significant antitumor effect. However, the efficacy of CD/5-FC therapy was not enhanced when combined with RIT, probably due to poor accumulation of the mAb as the tumor/blood ratio never exceeded 1.


CONCLUSIONS
These findings indicate that CD/5-FC gene therapy for prostate cancer may function with enhanced antitumor effect when combined with external beam radiation. However, combining CD/5-FC gene therapy and RIT using an anti-PSA mAb may not be effective because of insufficient accumulation of the mAb at the target tumors.
Kato
Hiroaki
H
Departments of Urology and Nuclear Medicine, Kanazawa University School of Medicine, Kanazawa, Japan.
Koshida
Kiyoshi
K
Yokoyama
Kunihiko
K
Mizokami
Atsushi
A
Namiki
Mikio
M
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000494:pharmacology*; D005472:Fluorouracil / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D009700:Nucleoside Deaminases / Q000235:genetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods; D011878:Radiotherapy / Q000379:methods; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000963:Antimetabolites; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil