Increased Cytopathic Effect of Replicating Adenovirus Expressing Adenovirus Death Protein

다국어 초록 (Multilingual Abstract)

Purpose: Replication-competent adenoviruses (Ads)are promising new modalities for the treatment of cancer.Selective replication of a viral agent in tumor may leadto improved efficacy over non-replicating Ads due to viralmultiplication, lysis of the infected cancer cell and spreadto surrounding cells. In our previous studies it wasshown that the E1B 55 kD-deleted Ad (YKL-1) exhibitstumor specific replication and cell lysis, but with reducedcytolytic effects compared to the wild type adenovirus(Int J Cancer 2000;88:454-463). Thus, improving thepotency of oncolytic Ads remains an important goal forcancer gene therapy. To increase the oncolytic ability ofYKL-1, an adenovirus death protein (ADP) gene wasreintroduced under the control of a CMV or MLP promoterat the E3 region of the YKL-1, generating an YKL-cADPand YKL-mADP, respectively.Materials and Methods: The in vitro cytolytic effect ofADP expressing Ads was evaluated by MTT assay, andthe induction of apoptosis by ADP expressing Ads wasexamined by TUNEL analysis. Finally, the antitumor effectof ADP expressing Ads was demonstrated in C33A xenografttumor model.Results: The YKL-cADP exerted a markedly enhancedcytolytic effect against H460 and SK-Hep1 cancer celllines. The TUNEL assay indicated that the ADP-mediatedcytotoxicity was largely driven by apoptosis. Finally, theYKL-cADP showed a superior antitumor effect than theYKL-1 or YKL-mADP in C33A xenografts.Conclusion: These lines of evidence demonstrate thatthe YKL-cADP induces efficient cell lysis, which is criticalfor the addition of therapeutic value to replicating Ads incancer gene therapy. (Cancer Res Treat. 2003;35:425-432)