Expression of P53, or targeting towards EGFR, enhances the oncotytic potency of conditionalty repticative adenovirus against neuroblastoma

Background Advanced stage and relapsing neuroblastoma (NB) has a poor prognosis with frequent treatment failures, warranting new treatment options and enhanced local tumor control. Treatment with conditionally replicative adenoviruses (CRAds) has shown effectiveness in various preclinical cancer models, but has not yet been evaluated for local control of NB. Here, we tested the efficacy of the CRAd Ad Delta 24 and of two Ad Delta 24 derivatives against NB. Derivative Ad Delta 24-425S11 infects cells deficient in coxsackie/adenovirus receptor (CAR) via the epidermal growth factor receptor (EGFR). Derivative Ad Delta 24-p53 expresses the tumor suppressor protein p53 to promote oncolysis. Methods Expression of CAR and EGFR, and p53 pathway and DNA damage responses were analyzed in six NB cell lines and two xenografts derived from primary NB using immunohistochemistry, reporter gene transactivation, Western blot and fluorescence-activated cell sorting (FACS) analysis. Efficacy of Ad Delta 24, Ad Delta 24-425S11 and Ad Delta 24-p53 against NB; was evaluated in vitro by cell viability analysis and in vivo by monitoring subcutaneous xenograft tumor growth in mice and by histological analysis of treated tumors. Results Neuroblastoma cell lines were sensitive to oncolysis by Ad Delta 24, with a higher susceptibility of those with functional p53 and intact DNA damage responses. Compared to Ad Delta 24, Ad Delta 24-p53 exhibited enhanced oncolytic potency on all NB cell lines independent of their p53 status and Ad Delta 24-425S11 was more effective against CAR-low IGR-NB8 cells. Moreover, five daily intratumoral injections of 101 plaque-forming units (pfu) of Ad Delta 24-p53 or Ad Delta 24-425S11 into subcutaneous IGR-NB8 and IGR-N91 xenografts at an advanced tumor stage yielded significant tumor growth delays (TGD). In contrast, at this dose, Ad Delta 24 did not cause significant TGD of neuroblastoma xenografts. Injection of Ad Delta 24-p53 was associated with extensive cell lysis, apoptotic cell death, and fibrous fascicles in the tumors. Conclusion CRAds expressing p53 and targeted towards EGFR appear promising new agents for local control in the treatment of neuroblastoma. Copyright (c) 2005 John Wiley & Sons, Ltd.