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, Chris H.; Hull, Gerald W.; Lee, H. M.; Hu, Jingyuan; Wang, J.; McCurdy, Mark A.; Shimura, Satoru; Yang, Guang; Timme, Terry L.; Thompson, Timothy C.

doi:10.1038/sj.gt.3300834

Cited by 152 publications

(113 citation statements)

References 34 publications

(44 reference statements)

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“…4 The adenoviral vector expressing the HSV-tk gene, AdHSV-tk has also been previously described. 1 As controls we used either AdHSV-tk vector followed by PBS instead of ganciclovir (GCV) or Ad/ CMV/bgal.…”

Section: Cells and Adenovirusmentioning

confidence: 99%

“…3 Ad/CMV/bgal was used as a control vector at 5610 8 PFU. All vector injections were performed as previously described 4 in a volume of 25 ml. Pre-existing lung metastases were established by tail vein injection of 100 000 cells (in 100 ml) at the same time as the orthotopic inoculation of 5000 RM-9 cells into the prostate.…”

Section: Cells and Adenovirusmentioning

confidence: 99%

“…Animals with pre-existing metastases were killed on the eighth day after vector injection at which time the lungs were weighed, ®xed in Bouin's ®xative, and visible lung metastases counted with the aid of a dissecting microscope at 106 magni®cation as previously described. 4,8 To block NK activity mice were injected with 5000 RM-9 cells orthotopically and 100 000 cells via the tail vein. Five days later one group received an intraperitoneal injection of 100 mg of anti-asialo-GM1 serum in 0.15 ml.…”

Section: Cells and Adenovirusmentioning

confidence: 99%

“…As previously demonstrated there was no effect on IL-12 mediated anti-tumor or anti-metastatic activity observed in mice injected with normal mouse IgG instead of anti-asialo-GM1 serum. 4 All mice were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care and all animal studies conducted in accordance with the principles and procedures outlined in the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.…”

Section: Cells and Adenovirusmentioning

confidence: 99%

“…These activities lead to enhanced survival in treated animals as well as to signi®cant suppression of pre-established lung metastases. 4 These studies have led us to the obvious consideration of testing combination AdHSV-tk GCV IL-12 gene therapy protocols in our preclinical models. Combination gene therapy has recently become an area of focus for many groups and early experimental data indicate that speci®c gene therapy strategies involving combinations of immunostimulatory molecules can generate additive and/or synergistic therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

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

Nasu

Bangma

Hull

et al. 2001

Prostate Cancer Prostatic Dis

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We previously demonstrated signi®cant 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 preestablished lung metastases models of prostate cancer. Combined treatment with a single injection of optimal doses of AdHSV-tk GCV or AdmIL-12 led to signi®cantly 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 signi®cantly 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-in®ltrating 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 in®ltration for all four of these immune cells that was in general mimicked by combination therapy. Further analysis of the accumulation of transforming growth factor-b1 (TGF-b1) 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-b-gal injections. Interestingly, local injection with AdHSV-tk GCV induced signi®cant splenocyte-derived NK cell cytolytic

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Section: Cells and Adenovirusmentioning

confidence: 99%

Section: Cells and Adenovirusmentioning

confidence: 99%

Section: Cells and Adenovirusmentioning

confidence: 99%

Section: Cells and Adenovirusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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