Gene therapy utilizing tumor suppressor gene p53 has been tested in a number of cancers in both preclinical models and clinical trials. Despite the ability of p53 to significantly inhibit tumor growth in preclinical models, it has met with more limited clinical success. This is due, in part, to the observation that a substantial fraction of tumors are resistant to the effects of p53 expression. We have tested whether combination therapy with Thoc1/p84 and p53 is more effective than single gene therapy in a p53-resistant tumor model of human pancreatic adenocarcinoma. Infection with Thoc1/p84 and p53 adenovirus inhibits pancreatic cancer cell growth in vitro and in vivo to a greater extent than treatment with either one alone at the same total viral dose. Similar results are observed with Thoc1/p84 and Rb1 gene therapy. The data support the use of therapy that targets both the p53 and Thoc1/p84 pathways in tumors that are resistant to perturbation of the p53 pathway alone.

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