The p53-independent tumoricidal activity of an adenoviral vector encoding a p27-p16 fusion tumor suppressor gene

We describe here that DE1-adenovirus vectors (AV) expressing a p27-p16 fusi on molecule, termed W9, induce tumor cell apoptosis when overexpressed in a wide range of tumor cell types. However, in primary human cells derived fr om a variety of normal tissues, AV-W9 induced minimal apoptosis. In tumor c ells AV-W9 demonstrated 5- to 50-fold greater tumoricidal activity than eit her of the parental molecules p16 and p27. In these studies, AV-W9 elicited apoptosis independent of the p53 and Rb status of the tumor cells. In seve ral murine tumor models AV-W9 demonstrated p53-independent antitumor activi ty. It completely prevented tumor formation in two ex vivo models, whereas the parental molecules resulted in partial protection. Furthermore, AV-W9 i nduced tumor regression or suppressed tumor growth when introduced intratum orally into preestablished tumors in mice. This effect may be mediated thro ugh tumor cell apoptosis or antiangiogenic activity of AV-W9. Thus, this no vel chimeric molecule is more potent and capable of killing a broader spect rum of tumors than the parental p16 and p27 molecules independent of the tu mor cell p53 and phenotype and represents a powerful new therapeutic agent for cancer gene therapy.