Combination gene therapy with adenoviral vector-mediated HSV-tk + GCV and IL-12 in an orthotopic mouse model for prostate cancer

Y. Nasu, C. H. Bangma, G. W. Hull, G. Yang, J. Wang, S. Shimura, M. A. Mccurdy, S. Ebara, H. M. Lee, T. L. Timme, T. C. Thompson

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28 Citations (Scopus)

Abstract

We previously demonstrated significant therapeutic activities associated with adenoviral vector-mediated Herpes Simplex Virus/thymidine kinase (AdHSV-tk) with ganciclovir (GCV) in situ gene therapy in the RM-1 orthotopic mouse prostate cancer model and interleukin-12 (AdmIL-12) in situ gene therapy in the RM-9 orthotopic mouse prostate model for prostate cancer. In both protocols, local cytotoxicity and activities against pre-established lung metastases were demonstrated. To test whether combined AdHSV-tk + GCV + IL-12 gene therapy would lead to enhanced therapeutic effects when compared to either treatment alone, we used RM-9 mouse prostate cancer cells in both orthotopic and pre-established lung metastases models of prostate cancer. Combined treatment with a single injection of optimal doses of AdHSV-tk + GCV or AdmIL-12 led to significantly increased suppression of orthotopic tumor growth. IL-12 gene therapy alone was more effective than AdHSV-tk + GCV in suppressing spontaneous lymph node metastases and pre-established lung metastases but combination gene therapy did not result in additional anti-metastatic activities. Combination gene therapy also did not achieve significantly better animal survival compared to AdHSV-tk + GCV or AdmIL-12 alone. Analysis of localized antitumor activities demonstrated that AdHSV-tk + GCV therapy induced higher levels of necrosis compared to AdmIL-12 or combination therapy. However, both treatments alone and combination therapy produced similar increases in apoptotic index. To address the possible mechanisms of locally co-operative cytotoxic activities, we analyzed the systemic natural killer (NK) response and the numbers of tumor-infiltrating immune cells using quantitative immunohistochemical analysis. AdHSV-tk + GCV therapy alone led to detectable increases in iNOS-positive cells, CD4 + and CD8 + T-cells and moderately increased numbers of F4/80 (macrophage selective)-positive cells within treated tumors. In contrast, AdmIL-12 elicited a highly robust pattern of tumor infiltration for all four of these immune cells that was in general mimicked by combination therapy. Further analysis of the accumulation of transforming growth factor-β1 (TGF-β1) immunohistochemical staining demonstrated that AdHSV-tk + GCV treatment, but not AdmIL-12 treatment, produced cancer cell-associated increases in this cytokine relative to control Ad-β-gal injections. Interestingly, local injection with AdHSV-tk + GCV induced significant splenocyte-derived NK cell cytolytic activities with maximal response 7 days following treatment, whereas AdmIL-12 injection produced significantly higher NK activity with maximal response 2 days following injection. The combined treatment produced a higher systemic NK response over the 14-day treatment period. Depletion of NK cells in vivo demonstrated that this immunocyte subpopulation was responsible for early locally cytotoxic activities induced by AdHSV-tk + GCV but not AdmIL-12 and that NK activities were largely responsible for activities against pre-established metastases generated by both gene therapy protocols.

Original languageEnglish
Pages (from-to)44-55
Number of pages12
JournalProstate Cancer and Prostatic Diseases
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 1 2001

Keywords

  • Antimetastatic activity
  • Gene therapy
  • Interleukin-12
  • Orthotopic tumor model
  • Prostate cancer
  • Thymidine kinase

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

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  • Cite this

    Nasu, Y., Bangma, C. H., Hull, G. W., Yang, G., Wang, J., Shimura, S., Mccurdy, M. A., Ebara, S., Lee, H. M., Timme, T. L., & Thompson, T. C. (2001). Combination gene therapy with adenoviral vector-mediated HSV-tk + GCV and IL-12 in an orthotopic mouse model for prostate cancer. Prostate Cancer and Prostatic Diseases, 4(1), 44-55. https://doi.org/10.1038/sj.pcan.4500494