In vitro and clinical studies of gene therapy with recombinant human adenovirus-p53 injection for oral leukoplakia

Abstract

Purpose: Oral leukoplakia is a well-recognized precancerous lesion of squamous cell carcinoma. When accompanied with abnormal p53 expression, it suffered a higher risk of canceration. The present study was carried out to test whether the recombinant human adenovirus-p53 could introduce wild-type p53 gene to oral leukoplakia cellsand induce cell cycle arrest and apoptosis. Experimental Design: We select p53(-) oral dysplastic keratinocyte POE-9n, to observe the growth inhibition, cell cycle change, apoptosis-induced effects, and elaborate the corresponding molecular mechanism of recombinant adenovirus-p53 on POE-9n cells. Meanwhile, we evaluate the feasibility, safety, and biological activity of multipoints intraepithelial injectionsof recombinant adenovirus-p53 in 22 patientsw ith dysplastic oral leukoplakia. Results: Exogenous p53 could be successfully transduced into POE-9n cells by recombinant adenovirus-p53. The optimal infecting titer in thiss tudy wasmultiplicity of infection (MOI) = 100. Recombinant adenovirus-p53 could strongly inhibit cell proliferation, induce apoptosis, and arrest cell cycle in stage G1 in POE-9n cellsby inducing p21CIP/WAF and downregulating bcl-2 expression. In the posttreatment patients, p53 protein and p21CIP/WAF protein expression were significantly enhanced, yet bcl-2 protein presented low expression. Sixteen patients showed clinical response to the treatment, and 14 patients showed obvious histopathologic improvement. Conclusion: Intraepithelial injectionsof recombinant human adenovirus-p53 were safe, feasible, and biologically active for patients with dysplastic oral leukoplakia. © 2009 American Association for Cancer Research.