Improved Antitumor Effect of Survivin Responsive Conditional Replication Adenovirus in Combination with Cisplatin in Lung Cancer

Abstract

Object: A chemotherapy drug such as cisplatin or diamminedichloroplatinum (DDP) is an alkylating agent that is widely used to treat many cancers despite its associated severe side effects. Biotherapy involving oncolytic adenoviruses also has proven anti-tumor efficacy. Survivin, an inhibitor of apoptosis is highly expressed in tumor cells. The aim of this study was to examine the synergistic effects of combined therapy including Survivin-responsive adenovirus and cisplatin in the treatment of lung cancer and to further reveal the mechanism involved. Methods: Two lung cancer cell lines, NCI-H292 and NCI-H66, were obtained from the cell collections center at CAS-China. A Survivin-responsive conditionally replicating adenovirus (CRAd) with a deleted E1B region was developed in our laboratory. The anti-tumor efficacy of combined in vitro and in vivo treatment (DDP plus CRAd) was assessed with MTS assays and a subcutaneous mouse model, respectively. The expression of Coxsackie adenoviral receptor (CAR) on cancer cell surfaces was determined through RT-PCR analysis. Results: The MTS assays revealed maximal tumor inhibition rates of 70% and 60% obtained when DDP and CRAd were used at doses of 64 μg/ml and 800 MOI, respectively. Nearly identical inhibition was observed with a combined treatment approach (DDP+CRAd) with lower doses of DDP (4 μg/ml) and CRAd (100 MOI). In vivo studies also revealed that tumor suppression was significantly higher in the combined treatment group. RT-PCR analysis showed that CAR expression was much higher in the combined treatment groups. Conclusion: Our study indicates that the combined treatment approach, including survivin promoter-regulated CRAd and DDP, is therapeutically more effective against lung cancer not only because of the synergistic tumorinhibition of the two treatments but also because of the additional tumor-specificity of CRAd resulting from Survivin promoter insertion.