Development of the PKR-dependent replicating adenovirus

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The design of double-stranded RNA-activated protein kinase (PKR)-depended replicating adenovirus is described as a new approach to cancer gene therapy. The virus-associated type I (VAI) RNA cannot activate PKR, although it binds to the protein and thereby prevents its activation by authentic dsRNA. In this study, we engineered the conditionally replicative adenovirus (CRAD) with the modification of VAI gene and investigated the utility of CRAD targeted to pancreatic cancer. We constructed a modificated VAI gene (mVAI) which the central domain was deleted. This mVAI was replaced its own endogenous VAI gene harboring in adenovirus type 5 genome (Adv-mVAI). When the cytolytic activity of Adv-mVAI was evaluated, it failed to inhibit the growth of the pancreatic cancer cell; BxPC-3 with wild K-ras. Interestingly, we demonstrated that the transduction of active-formed ras into BxPC-3 cells by the infection of retroviruses expressing H-ras/V12 was sufficient to induce the cytolytic activity of Adv-mVAI. In addition, the cytolytic activity of Adv-mVAI was observed in the pancreatic cancer cell; AsPC-1 with mutant K-ras. However, this cytolytic activity of Adv-mVAI was reduced after interferon treatment.These data indicate that the activation of ras and interferon will be useful for controlling the anti-tumor effect of adenovirus harboring the variant VAI gene.