P21 gene expression as an indicator for the activity of adenovirus-p53 gene therapy in non-small cell lung cancer patients

Alterations in the tumor suppressor gene p53 lead to impaired cell cycle co ntrol, allowing for the development and growth of tumors. To restore a loss of p53 function, we performed a phase I study of intratumoral gene therapy with adenovirus expressing wild-type p53 in patients with non-small cell l ung cancer carrying mutations in the p53 gene. Furthermore, in a phase II s tudy, gene therapy was complemented with simultaneous cisplatin/vinorelbine treatment. Biopsies were obtained from all treated patients before and 24- 48 hours after gene therapy to study changes in the expression of p53 targe t genes. We report here that in most of the cases, the target gene p21 was up-regulated, especially when injection of higher doses of p53-expressing a denovirus was combined with simultaneous chemotherapy, whereas Pig3, previo usly reported to be highly up-regulated by p53, generally did not show a cl ear increase. Interestingly, a clear p21 gene response was observed only in tumors showing stabilization or regression. We conclude that p21 appears t o be up-regulated after adenovirus-mediated p53 gene transfer and is the mo st sensitive marker tested for biological response to gene therapy in the s mall cohort of non-small cell lung cancers that were studied.