Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model

Yasutomo Nasu, C. H. Bangma, G. W. Hull, H. M. Lee, J. Hu, J. Wang, M. A. McCurdy, S. Shimura, G. Yang, T. L. Timme, T. C. Thompson

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Interleukin-12 (IL-12) can elicit potent antitumoral effects that involve the recruitment of specific immune effector cells. We investigated the efficacy o a single injection of a recombinant adenovirus expressing murine IL-12 (AdmIL-12) directly into orthoptic mouse prostrate carcinomas generated from a poorly immunogenic cell line (RM-9) derived from the mouse prostrate 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 orthoptic 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 defected 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 anti-asialo-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 anti-tumor 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.

Original languageEnglish
Pages (from-to)338-349
Number of pages12
JournalGene Therapy
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 1999
Externally publishedYes

Fingerprint

Interleukin-12
Adenoviridae
Genetic Therapy
Prostatic Neoplasms
Neoplasm Metastasis
Lung
Injections
Growth
Orthoptics
Natural Killer Cells
Neoplasms
Nitric Oxide Synthase
Macrophages
Viruses
T-Lymphocytes
Cytotoxic T-Lymphocytes
Tumor Burden
Carcinoma
Cell Line
Serum

Keywords

  • Gene therapy
  • Interleukin-12
  • Metastasis
  • Orthotopic tumor model
  • Prostate cancer

ASJC Scopus subject areas

  • Genetics

Cite this

Adenovirus-mediated interleukin-12 gene therapy for prostate cancer : Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model. / Nasu, Yasutomo; Bangma, C. H.; Hull, G. W.; Lee, H. M.; Hu, J.; Wang, J.; McCurdy, M. A.; Shimura, S.; Yang, G.; Timme, T. L.; Thompson, T. C.

In: Gene Therapy, Vol. 6, No. 3, 03.1999, p. 338-349.

Research output: Contribution to journalArticle

Nasu, Y, Bangma, CH, Hull, GW, Lee, HM, Hu, J, Wang, J, McCurdy, MA, Shimura, S, Yang, G, Timme, TL & Thompson, TC 1999, 'Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model', Gene Therapy, vol. 6, no. 3, pp. 338-349. https://doi.org/10.1038/sj.gt.3300834
Nasu, Yasutomo ; Bangma, C. H. ; Hull, G. W. ; Lee, H. M. ; Hu, J. ; Wang, J. ; McCurdy, M. A. ; Shimura, S. ; Yang, G. ; Timme, T. L. ; Thompson, T. C. / Adenovirus-mediated interleukin-12 gene therapy for prostate cancer : Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model. In: Gene Therapy. 1999 ; Vol. 6, No. 3. pp. 338-349.
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