Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells

The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a human pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions; after a 5-day incubation period, the anticancer activity was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Each 50% inhibitory concentration was calculated based on the dose-response curves. The agents showing a high degree of effectiveness on NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT-11); conversely, cyclophosphamide and paclitaxel showed a low degree of effectiveness. Based on these data, an isobologram was performed to investigate the interaction between AdCAp53 and some anticancer agents. A supra-additive effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI-H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299 cells. No drug showed any subadditive or protective effects. These findings suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11 had a significant antitumoral effect on H157 cell xenografts of nude mice in vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for the combination of chemotherapy and gene therapy for non-small cell lung cancer.