Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model.
Interleukin-12 (IL-12) can elicit potent antitumoral effects that involve the recruitment of specific immune effector cells. We investigated the efficacy of a single injection of a recombinant adenovirus expressing murine IL-12 (AdmIL-12) directly into orthotopic mouse prostate carcinomas generated from a poorly immunogenic cell line (RM-9) derived from the mouse prostate reconstitution system. Significant growth suppression (> 50% reduction of tumor weight) and increased mean survival time (23.4 to 28.9 days) were observed compared with controls. Suppression of pre-established lung metastases was also observed following the injection of AdmIL-12 into the orthotopic tumor. Cytolytic natural killer cell activity was markedly enhanced 1-2 days after virus injection. Immunohistochemical analysis showed significantly elevated intratumoral infiltration of CD4+ and CD8+ T cells 7 days after virus injection. However, splenocyte-derived cytotoxic T lymphocytes were not detected during the 14 days following treatment. Increased numbers of nitric oxide synthase-positive macrophages were seen in the AdmIL-12 treated group 7 days following injection. Systemic inhibition of natural killer cells with antiasialo-GM1 serum led to increased numbers of lung metastases in AdmIL-12-treated orthotopic tumors but did not affect local tumor growth. In this model system the antitumor effects of a single injection of adenovirus-mediated IL-12 appears to be based to a large extent on the activation of nitric oxide synthase in macrophages and possibly T cell activities, whereas the relatively early cytolytic activity of natural killer cells are largely but not exclusively responsible for the antimetastatic effects.
Nasu
Y
Y
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Bangma
C H
CH
Hull
G W
GW
Lee
H M
HM
Hu
J
J
Wang
J
J
McCurdy
M A
MA
Shimura
S
S
Yang
G
G
Timme
T L
TL
Thompson
T C
TC
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000032:analysis / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*
D018664:Interleukin-12