Oncolytic potential of E1B 55 kDa-deleted YKL-1 recombinant adenovirus: Correlation with p53 functional status

YKL-1, E1B 55 kDa-deleted recombinant adenovirus vector, capable of harbori ng a transgene casette of up to 4.9 kb, was newly constructed by reintroduc ing E1A and E1B 19 kDa into E1/E3-deleted adenoviral vector with a homologo us recombination in E. coli. Virus replication and cytotoxicity were dramat ically attenuated in all 3 different types of normal human cells. In contra st, YKL-1 efficiently replicated and induced cytotoxicity in most cancer ce lls, especially Hep3B and C33A cells with an inactivating p53 mutation. How ever, both H460 and HepG2, exhibited intermediate sensitivity to YKL-1, whi ch was between that of Hep3B or C33A and normal human cells. The YKL-1 and DNA damaging agent, camptothecin effectively induced p53 in H460 and HepG2 as well as in normal cells. Furthermore, YKL-1 effectively prohibited both Hep3B and C33A tumor growth in nu/nu mice in a dose-dependent manner. HIE s taining and TUNEL assay indicated a largely distributed necrotic area and a poptosis on its periphery, This study, therefore, indicates that YKL-1, pos sesses promising potential as an oncolytic adenoviral vector, which acts pa rtially in a p53-dependent manner. Int. J. Cancer 88:454-463, 2000. (C) 200 0 Wiley-Liss, Inc.