Cancer gene therapy mediated by CTS1, a p53 derivative: Advantage over wild-type p53 in growth inhibition of human tumors overexpressing MDM2

Recently, a new p53 derivative has been designed, namely chimeric tumor sup pressor 1 (CTS1), in which the p53 domains that are known to mediate p53 in activation have been replaced. In this study, the antitumoral activity of C TS1 mediated by adenovirus vector has been evaluated in comparison with a p 53 adenovirus vector in various human tumor cell lines. In vitro, in terms of cell growth inhibition, the CTS1 vector was significantly (P < .01) more efficient (2- to 7-fold) than the p53 vector in tumor models overexpressin g an inhibitor of p53, murine double minute-2. This result was confirmed in vivo in a pre-established tumor developed in nude mice. In an osteosarcoma model overexpressing murine double minute-2, we have shown a significantly (P < .05) higher tumor growth delay with the CTS1 vector compared with the p53 vector (25.6 days compared with 12.4 days). Furthermore, both in vitro and in vivo, we have shown that this higher inhibition of tumor growth wit h the CTS1 vector was correlated with a higher induction of apoptosis. Ther efore, CTS1 is a potentially improved tumor suppressor gene for the treatme nt of human tumors resistant to wild-type p53 gene therapy.