Abstract:

Objective To evaluate the antitumor effect of oncolytic adenovirus expressing human IL-18 gene on malignant melanoma implanted in nude mice. Methods BALB/c nude mice were subcutaneously inoculated with A375 cells to establish a model of malignant melanoma. When the volume of implanted tumor reached 100 - 150 mm3, murine models were randomly divided into three groups to receive a 3-day intratumoral injection of IL-18 gene-expressing human oncolytic adenovirus named ZD55-IL-18, IL-18 gene-expressing adenovirus named Ad-IL-18, phosphate buffer saline （PBS）, respectively. The tumor size was measured at an interval of 4 days for 9 weeks. Hematoxylin and eosin （HE） staining was performed to observe the morphological changes of tumor cells. The protein expression of IL-18 and E1A，microvessel density in tumor tissue，and apoptosis of tumor xenografts were detected by immuno- fluorescence assay, immunohistochemistry and in situ end labeling technique （TUNEL）, respectively. Results The treatment with ZD55-IL-18 significantly inhibited the growth of tumor. Forty-four days after the treatment, the mean tumor volume was 1039.378 ± 29.67 mm3 in ZD55-IL-18-treated mice, significantly smaller than that in Ad-IL-18 treated mice （2900.46 ± 62.65 mm3） and PBS-treated mice （3980.24 ± 63.78 mm3）. HE staining showed that the nuclei of tumor cells were heavily stained with few nucleoli in ZD55-IL-18-treated mice. Increased positivity rate of IL-18 was noticed in ZD55-IL-18-treated mice vs. AD55-IL-18-treated mice （83.4% ± 3.2% vs 24.4% ± 2.1%, P < 0.01）. Moreover, immunofluorescence assay revealed the presence of E1A protein in tumor tissue. A decrease was found in the microvessel density in ZD55-IL-18-treated mice compared with the PBS-treated mice （P < 0.01）. The apoptosis rate in tumor cells from high to low was 86.28% ± 3.25% in ZD55-IL-18-treated mice, 43.67% ± 3.46% in Ad-IL-18-treated mice, and 10.73% ± 2.48% in PBS-treated mice; there was a significant difference between the three groups （all P < 0.05）. Conclusion The oncolytic adenovirus expressing human IL-18 gene, ZD55-IL-18, has a significant inhibitory effect on the growth and metastasis of malignant melanoma implanted in nude mice.