Synergistic inhibition of human lung cancer cell growth by adenovirus-mediated wild-type p53 gene transfer in combination with docetaxel and radiation therapeutics in vitro and in vivo

Chemotherapy given sequentially or concurrently with external beam radiatio n therapy has emerged as a standard for the treatment of locally advanced l ung cancer. Gene therapy by adenovirus-mediated wild-type p53 gene transfer has been shown to inhibit lung cancer growth in vitro, in animal models, a nd in human clinical trials. However, no information is available on the co mbined effects of p53 gene transfer, chemotherapy, and radiation therapy on lung cancer growth in vitro and in vivo. Therefore, we developed two-dimen sional and three-dimensional isobologram modeling and statistical methods t o evaluate the synergistic, additive, or antagonistic efficacy among these therapeutic agents in human non-small cell lung cancer cell lines A549, H46 0, H322, and H1299, at the ID50 and ID80 levels. The combination of these t hree therapeutic agents exhibited synergistic inhibitory effects on tumor c ell growth in all four cell lines at both the ID50 and the ID80 levels in v itro. In mouse models with H1299 and A549 xenografts, combined treatment sy nergistically inhibited tumor growth in the absence of any apparent increas e in toxicity, when compared with other treatment and control groups. Toget her, our findings suggest that a combination of gene therapy, chemotherapy, and radiation therapy may be an effective strategy for human cancer treatm ent.