Adenovirus-p53-mediated gene therapy of anaplastic large cell lymphoma with t(2;5) in a nude mouse model

Abstract

Adenovirus-p53-mediated apoptosis has been extensively evaluated in animal xenografts derived from human epithelial tumors and recently began testing in phase I clinical trials, but has not been evaluated for lymphoid malignancies. Cell lines derived from anaplastic large cell lymphoma (ALCL) carrying the t(2;5) translocation are efficiently transduced by adenoviral vector expressing p53 and undergo apoptosis. To test the in vivo efficiency of adenovirus-mediated-p53 expression and apoptosis induction, SUDHL-1 cells (derived from human ALCL) were injected subcutaneously into athymic nude mice. Cells from the xenograft had typical morphology of human ALCL by standard hematoxylin-eosin staining, CD5⁺, CD45⁺ and CD30⁺ immunophenotype, the t(2;5) translocation by PCR. Six tumors from an initial set of mice were evaluated for apoptosis by TUNEL and for necrosis by hematoxylin-eosin staining 48–72 h after injection with 1 × 10⁸ p.f.u. of AdWTp53 (adenoviral vector expressing p53), of AdNull (adenoviral vector backbone) and PBS (mock), respectively. TUNEL staining was positive only in tumors injected with AdWTp53 and was mainly localized around the needle track. Differences of the means of the counts of the necrotic cells were statistically significant at P = 0.02 between AdWTp53 and mock and only borderline between AdWTp53 and AdNull. Twenty-three tumors from a separate set of mice were subsequently injected with AdWTp53, AdNull and PBS and evaluated for in vivo tumor response. Three total injections of viral vectors (1 × 10⁸ p.f.u.) and PBS were given every 48–72 h. Only tumors injected with AdWTp53 showed tumor growth inhibition with a mean final tumor volume that was statistically significantly smaller than AdNull (P = 0.007) and mock (P = 0.002). Based on these results we foresee a potential application of adenovirus-mediated p53 apoptosis as gene therapy of lymphomas.