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 language | English |
|---|---|
| Pages (from-to) | 338-349 |
| Number of pages | 12 |
| Journal | Gene Therapy |
| Volume | 6 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 1999 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Adenovirus-mediated interleukin-12 gene therapy for prostate cancer
T2 - Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model
AU - Nasu, Yasutomo
AU - Bangma, C. H.
AU - Hull, G. W.
AU - Lee, H. M.
AU - Hu, J.
AU - Wang, J.
AU - McCurdy, M. A.
AU - Shimura, S.
AU - Yang, G.
AU - Timme, T. L.
AU - Thompson, T. C.
PY - 1999/3
Y1 - 1999/3
N2 - 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.
AB - 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.
KW - Gene therapy
KW - Interleukin-12
KW - Metastasis
KW - Orthotopic tumor model
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=0032996037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032996037&partnerID=8YFLogxK
U2 - 10.1038/sj.gt.3300834
DO - 10.1038/sj.gt.3300834
M3 - Article
C2 - 10435084
AN - SCOPUS:0032996037
VL - 6
SP - 338
EP - 349
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 3
ER -