Midkine promoter-based conditionally replicative adenovirus for malignant glioma therapy

Little is known concerning promoters or gene therapy specific for malignant glioma. To explore the potential use of midkine promoter in gene therapy for malignant glioma, we constructed a midkine promoter-based conditionally replicating adenovirus (Ad-MK). Midkine was overexpressed in malignant glioma tissues but cyclooxygenase-2 was not. The midkine promoter activity of the 600-bp fragment was 2 orders of magnitude higher in midkine-positive glioma cells than in midkine-negative primary normal brain cells. Ad-MK showed strong oncolytic effects in midkine-positive glioma cells but did not exhibit cytotoxicity in midkine-negative primary normal brain cells. The cell-killing effect was evident in E3-intact Ad-MK more than in E3-deleted Ad-MK. In an animal experiment, Ad-MK completely eradicated midkine-positive glioma xenografts. These findings indicate that midkine promoter-based conditionally replicative adenovirus might be a promising new modality of gene therapy for malignant glioma.