Antitumor Activity of bax and p53 Naked Gene Transfer in Lung Cancer: In Vitro and In Vivo Analysis

Abstract

In vitro and in vivo data have demonstrated that virus-mediated p53 gene transfer can induce active cell death and lung tumor regression. In contrast, the therapeutic potential of bax, another apoptosis-inducing gene, has not been described. We compared p53 and bax cytotoxic effects by transient transfection of an average of 25 ± 5% of the H-322 and H-358 bronchioloalveolar carcinoma cell lines in vitro. Under these conditions, bax expression killed 70 to 90% of the transfected cells whereas p53 killed only 40% of them. The killing activity of both genes involved apoptosis, as shown by TUNEL staining. Surprisingly, BrdU incorporation indicated that the cells that did resist Bax toxicity were blocked in the pre-S phase of the cell cycle, a result expected for p53 only. In vivo, repeated injections of naked DNA encoding Bax or p53 inhibited the growth of 4-mm preestablished H-322 tumors in nude mice. Growth retardation only, and not inhibition, was observed in H-358, a poorly transfectable and rapidly growing tumor. These results indicate that Bax and p53 share a similar, strong antitumor activity in vivo, even if the former is a more potent inducer of apoptosis in vitro. On the basis of the widespread use of wild-type p53 for gene therapy of cancer, we compared the cytotoxic effect of bax and p53 on two lung cancer cell lines. Our results showed that bax was a stronger inductor of apoptosis than was p53 in vitro. In vivo, both genes shared a strong antitumor activity, inducing tumor growth inhibition in preestablished NSCLCC tumors. This suggested that bax is like p53, a good candidate for gene therapy applications.