INTRODUCTION OF CYTOKINE GENE INTO RAT NEOPLASM USING A HAND-HELD GENE GUN. II. LOCAL BOMBARDMENT OF IL-12 DNA PLASMID ON HEPATIC METASTASES

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Using a hand-held gene gun, we examined the effects of murine interleukin-12 IL-12) gene transfection on metastatic tumors. AH 130 cells at high (1×107) and low (1 ×106) doses were inoculated into the liver of Donryu rats through the portal vein. On the twelfth day following tumor inoculation, the hepatic surface was bombarded with IL-12 cDNA (4μg)-coated gold particles emitted by pressurized helium gas (300 psi). The corresponding amount of β-galactosidase (β-gal) cDNA was injected as a control in the same manner. The high-dose model was highly fatal and used for estimation of the survival rate. The low-dose model was investigated to evaluate alterations in the number of tumors, histological findings, and cytokine expression in the liver and spleen. Nontumor-bearing rats were employed for study of any adverse effects gene gun shots induce on body weight, peripheral blood cell counts, and liver function.<br>The IL-12 gene therapy was effective in terms of the 60-day survival rate (IL-12 50% vs. control 15%, p<0.05). Seven days after DNA transfer the average number of metastatic tumors in the liver increased in the control group, while it diminished in the gene therapy group. Histological examination revealed that most tumor cells in the control group were viable, whereas some of those in the IL-12 group underwent necrotic changes accompanied by massive lymphocytic infiltration. IL-12 and IFN-γ were expressed in the liver and spleen in greater amounts in the IL-12 group than in the control. No remarkable adverse effects were expressed in non-tumor-bearing rats undergoing gene bombazdment either with β-gal or IL-12 genes. Thus, this procedure may be applied clinically as a promising therapeutic option for metastatic tumor of the liver. A hand-held gene gun seems especially useful for transfection during laparotomy due to its ability to accurately and instantaneously inject exogenous genes under direct vision.

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