Fig. 1. Electroporation of interleukin 12 (IL-12) DNA compared with control DNA increases the level of IL-12 expression (picograms/milligrams total protein)

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Fig. 1. Electroporation of interleukin 12 (IL-12) DNA compared with control DNA increases the level of IL-12 expression (picograms/milligrams total protein) in tumors (A;P = .015) and induces interferon-gamma (IFN-γ) (picograms/milligrams total protein) (B;P = .041) in vivo. pCtrl and pIL-12 represent control and IL-12 DNA plasmids, respectively. Each bar represents an individual animal (n = 4 per group). The control DNA plasmid was prepared by deletion of the DNA fragment encoding IL-12 from the IL-12 DNA plasmid. Twenty micrograms of DNA plasmid was injected into each tumor by electroporation as described in “Materials and Methods,” and tumors were harvested 2 days after the second administration. From: Regression of Tumor Growth and Induction of Long-Term Antitumor Memory by Interleukin 12 Electro-Gene Therapy J Natl Cancer Inst. 2002;94(10):762-768. doi:10.1093/jnci/94.10.762 J Natl Cancer Inst | © Oxford University Press

Fig. 2. Interleukin 12 (IL-12) electro-gene therapy induces statistically significant therapeutic effects in mice (n = 5 in each group). Error bars represent mean ± 95% confidence intervals. The initial administration was performed when tumors reached 4–6 mm in diameter, and arrows indicate the times of administration. E+ = DNA delivered into tumors by electroporation; pCtrl and pIL-12 represent control and IL-12 DNA plasmids, respectively. A) Inhibition of tumor growth by IL-12. The tumor growth was statistically significantly inhibited by the IL-12 electro-gene therapy at the end of 3 weeks following the treatment (P = .025). B) Dose-dependent inhibition of tumor growth by IL-12. C) Increase in survival rate after IL-12 treatment (P = .031 for 20-μg pIL-12 dosage, and P = .022 for 40-μg pIL-12 dosage, respectively). Mice bearing tumors bigger than 2 cm in diameter were considered as dead mice. The average survival rate (95% confidence interval) for pIL-12 treatment groups and control group during the period of day 25 to 80 days after inoculation of tumor cells are 69.4 (53.7 to 85.1) for the dosage of 20 μg of pIL-12, 86.1 (71.8 to 100.4) for the dosage of 40 μg of pIL-12, and 27.7 (2.5 to 52.7) for the dosage of 40 μg of pCtrl, respectively. The mice at risk from groups receiving 20 μg of pIL-12, 40 μg of pIL-12, and 40 μg of pCtrl (control DNA) on day 30 were four of five, four of five, and four of five, respectively; on day 60: two of five, four of five, and zero of five, respectively; and on day 90: two of five, two of five, and zero of five, respectively. For both pIL-12 DNA treatment groups, there were 40% of mice with tumor regression, and the same mice survived for 365 days (data not shown). From: Regression of Tumor Growth and Induction of Long-Term Antitumor Memory by Interleukin 12 Electro-Gene Therapy J Natl Cancer Inst. 2002;94(10):762-768. doi:10.1093/jnci/94.10.762 J Natl Cancer Inst | © Oxford University Press

Fig. 3. Interleukin 12 (IL-12) electro-gene therapy induces expression of monokine induced by interferon-γ (Mig) and interferon inducible protein 10 (IP-10) in tumors (n = 3) as determined by northern blot analysis. Twenty micrograms of IL-12 DNA (lanes 4–6), 40 μg of IL-12 DNA (lanes 7–9), and 40 μg of control DNA (lanes 1–3) plasmids were injected into the tumors by electroporation. pCtrl and pIL-12 represent control and IL-12 DNA plasmids, respectively. Two days after the second administration, total RNA was prepared from tumor tissues and the expression of IP-10 and Mig were determined by northern blot analysis. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as an internal control (housekeeping gene) for the expression level of IP-10 and Mig. Each bar represents an individual animal (n = 3 per group). The level of IP-10 and Mig expression was quantified by scanning the expression signal intensity with a PhosphorImager analyzer (Model 445 SI; Molecular Dynamics, Sunnyvale, CA). To simplify the results, the level of GAPDH expression (control) was artificially defined as 1, and then the mean expression values (95% confidence interval) for Mig and IP-10 in the IL-12 DNA-treated groups were 15.4 (8.6 to 22.2) and 5.1 (2.7 to 7.5), respectively, and for the control groups were 1 (0.6 to 1.4) and 1 (0.7 to 1.3), respectively. From: Regression of Tumor Growth and Induction of Long-Term Antitumor Memory by Interleukin 12 Electro-Gene Therapy J Natl Cancer Inst. 2002;94(10):762-768. doi:10.1093/jnci/94.10.762 J Natl Cancer Inst | © Oxford University Press

Fig. 4. Vascular endothelial growth factor (VEGF) expression in the tumor (A) and serum (B) 2 days following the second administration of interleukin 12 (IL-12) gene (pIL-12) or control DNA (pCtrl). The second administration was performed 1 week after the first administration. Twenty micrograms of DNA plasmid was delivered into tumors by electroporation. Each bar represents an individual animal (n = 4 and n = 3 per group for the first and second administration, respectively). From: Regression of Tumor Growth and Induction of Long-Term Antitumor Memory by Interleukin 12 Electro-Gene Therapy J Natl Cancer Inst. 2002;94(10):762-768. doi:10.1093/jnci/94.10.762 J Natl Cancer Inst | © Oxford University Press