Role of Interferon-γ in Mediating the Antitumor Efficacy of Interleukin-12

Brunda, Michael J.; Luistro, Leopoldo; Hendrzak, Jill A.; Fountoulakis, Michael; Garotta, Gianni; Gately, Maurice K.

doi:10.1097/00002371-199502000-00001

Cited by 144 publications

(91 citation statements)

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“…[2][3][4] Induction of cytokines, such as interferon-g (IFN-g), IFN-inducible protein-10 (IP-10), and monokine induced by IFN-g (MIG), has also been implicated as a mechanism of antitumor activity of IL-12. 5,6 These diverse effects make IL-12 an attractive candidate as a therapeutic agent for cancer treatment. Systemic administration of IL-12 significantly suppressed the growth of established mouse tumors and prolonged the survival of tumor-bearing mice.…”

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confidence: 99%

Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]

et al. 2003

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Delivery of the interleukin-12 (IL-12) gene to solid tumors is a promising anticancer therapy. Vectors are currently being developed to achieve safe and effective intratumoral delivery of the IL-12 gene. Poly [D,L-2,4-diaminobutyric acid] (PDBA) is a novel gene carrier that was recently described. The goal of this study was to use this gene delivery system for treatment of solid tumors. To determine the optimal conditions for transfection, established B16F10-melanomas in C57BL/6 mice were treated with intratumoral injection of the PDBA/plasmid luciferase (pLuc) complex. We determined that the optimal complex composition was 50 mg/ml pLuc and 150 mg/ml PDBA. High levels of IL-12 protein were expressed in tumors after a single injection of PDBA/murine IL-12 (pmIL-12) complex, whereas serum levels of IL-12 in treated mice were below the limits of detection. IL-12 gene therapy with the PDBA system significantly inhibited tumor growth in comparison with the controls (Po.001). Moreover, both natural killer and cytotoxic T lymphocyte activities from draining lymph nodes of PDBA/pmIL-12-treated mice were increased substantially in comparison with those of controls (Po.05). These results suggest that PDBA-mediated IL-12 gene therapy is a potential strategy for treatment of patients with solid tumors.

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confidence: 99%

Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]

et al. 2003

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“…27 However, it has not been found to be as effective as IL-12 both in terms of its own production in vivo, as well as in terms of anti-tumor and anti-metastatic activity. 28 In the earlier paper, we reported that in vitro transfection of PAGA/pmIFN-␥ into cultured CT-26 tumor cells generates similar expression levels of mIFN-␥ in comparison with mIL-12 induced mIFN-␥. 29 In the present study, we found similar levels of mIFN-␥ when we administered PAGA/pmIL-12 and PAGA/pmIFN-␥ complexes into tumor-bearing BALB/c mice ( Figure 2).…”

Section: Discussionmentioning

confidence: 91%

“…It is evident that during early stages of IL-12 gene expression, APCs like dendritic cells and macrophages were one of the most active cells, which in part is due to their close relationship with elevated levels of endogenous IFN-␥ and TNF-␣. 15,28,33 Further downstream, events like induction of iNOS from macrophages would result in production of NO. 14,19 Elevated levels of nitric oxide thus indirectly confirmed the biological activity of IL-12, as well as macrophage infiltration.…”

Section: Discussionmentioning

confidence: 99%

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

et al. 2002

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“…delivery of IL-12 protein for 5 days with a dose of 1 g /mouse only led to temporary high levels of IFN -induction, which was almost undetectable 2 days after administration of IL -12 protein was stopped. 19 IFN -induction by IL -12 has been shown to correlate with the expression of interferon inducible protein ( IP) -10, mig, 18 and tumor regression. In another study, IFN -antibodies were shown to diminish the IL -12 therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

et al. 2001

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Gene therapy with IL -12 has been shown to elicit potent systemic antitumor response in a variety of tumors. Although direct intratumoral injection is the most commonly used delivery route for gene therapy of solid tumors, the skeletal muscle has been shown to be an ideal tissue for gene delivery to produce systemic gene expression. We have previously demonstrated that electroporation delivery of a reporter gene to muscle enhances the transfection efficiency and the level of gene expression by two to three logs. We report here that intramuscular ( i.m. ) injection of as little as 10 g of the IL -12 DNA plasmid followed by electroporation prevents squamous cell carcinoma ( SCCVII ) tumor establishment in up to 40% of experimental animals and reduces the volume of established tumors by 75% compared to controls ( P < .05 ) . By comparison, there was no difference in tumor growth observed between IL -12 injection alone and injection of empty vector with or without electroporation. The induction of antitumor activity by i.m. electroporation delivery of the IL -12 gene is associated with an increase in IL -12 expression in muscle and serum. The level of IL -12 expression in muscle and serum was 1500 pg / tibialias muscle and 170 pg / mL serum, respectively, at day 6, after the gene was delivered by electroporation. In contrast, the level of IL -12 when the gene was injected without electroporation was hardly detectable after subtracting the background level of IL -12 detected in naõ Ève mice. The high level of IL -12 expression led to a 170 -fold induction of IFN -expression in serum at day 6 after i.m. electroporation delivery of IL -12 DNA plasmid, which was equal to 1450 pg / mL in the serum. The induction of antitumor activity by i.m. electroporation delivery of the IL -12 gene also correlates with increased CD8 + T -cell population in peripheral blood but not in spleen. Our findings suggest that i.m. delivery of IL -12 gene using electroporation is an effective method of inducing a systemic antitumor response against SCC. Cancer Gene Therapy ( 2001 ) 8, 151 ± 157

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Role of Interferon-γ in Mediating the Antitumor Efficacy of Interleukin-12

Cited by 144 publications

References 0 publications

Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]

Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

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