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

Abstract

Abstract 10.1002/1097-0215(20001101)88:3<454::AID-IJC19>3.3.CO;2-K YKL‐1, E1B 55 kDa‐deleted recombinant adenovirus vector, capable of harboring a transgene casette of up to 4.9 kb, was newly constructed by reintroducing E1A and E1B 19 kDa into E1/E3‐deleted adenoviral vector with a homologous recombination in E. coli. Virus replication and cytotoxicity were dramatically attenuated in all 3 different types of normal human cells. In contrast, YKL‐1 efficiently replicated and induced cytotoxicity in most cancer cells, especially Hep3B and C33A cells with an inactivating p53 mutation. However, both H460 and HepG2 exhibited intermediate sensitivity to YKL‐1, which 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. H/E staining and TUNEL assay indicated a largely distributed necrotic area and apoptosis on its periphery. This study, therefore, indicates that YKL‐1, possesses promising potential as an oncolytic adenoviral vector, which acts partially in a p53‐dependent manner. Int. J. Cancer 88:454–463, 2000. © 2000 Wiley‐Liss, Inc.