Cytotoxicity of adenoviruses expressing the wild-type p53 gene to esophageal carcinoma cells is linked with the CAR expression level and indirectly with the endogenous p53 status

Abstract

We examined cytotoxic effects of adenoviruses (Ad) expressing the p53 gene (Ad-p53) in nine human esophageal carcinoma cell lines with respect to the Ad receptor expression and the endogenous p53 gene status. Ad-p53-mediated cytotoxicity was related with an expression level of the coxsackievirus adenovirus receptor (CAR) but not with that of CD51, both of which are type 5 Ad receptors. Contrary to earlier studies, we found that the cytotoxicity was greater in tumor cells with the wild-type p53 gene than in those with mutated p53. The cytotoxic activity of Ad defective of E1B55kDa molecules (Ad-delE1B55), however, was not linked with the CAR expression level or the endogenous p53 status. We noticed that the tumor cells with the wild-type p53 gene showed greater CAR expression levels, although transduction with Ad-p53 did not upregulate the CAR expression in the mutated cells. We also examined the Ad-53-mediated cytotoxicity in two kinds of paired fibroblasts, parent and immortalized with loss of the p53 functions, and showed that the CAR expression level was more influential than the endogenous p53 status in the cytotoxicity. These data suggest that CAR expression level is a better predictive marker than endogenous p53 status for Ad-p53-mediated cytotoxicity in esophageal carcinoma.

Combinatory cytotoxic effects produced by E1B-55kDa-deleted adenoviruses and chemotherapeutic agents are dependent on the agents in esophageal carcinoma

“…13 Our previous study also showed that Ad-GFP infectivity was not different between HFF and IF cells and that the p53 expression was induced by CDDP in HFF but not in IF cells, showing that the p53 function was lost in IF cells. 14 We found that the cytotoxicity of Ad-delE1B55 was greater in IF than in HFF cells (Figure 2b, P <0.05). HFF and IF cells were relatively resistant to type 5 Ad infection, and high MOIs were required for the cytotoxicity compared with the esophageal carcinoma cells tested.…”

Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells

“…Expression of the wt-p53 protein in tumor cells following Ad transfection may take a certain amount of time. Studies have demonstrated that p53 protein expression is initiated 3 h following rAd-p53 transfection, with an expression rate of approximately 50% at 12 h and a peak expression at 48-72 h (12)(13)(14). Based on these results, we selected a 72-h time point to detect all indicators following rAd-p53 infection.…”

“…It has also been approved as a treatment model for certain head and neck malignancies, including nasopharyngeal carcinoma (11). Previous studies have revealed that the peak time for wt-p53 expression following Gendicine treatment was 48-72 h after transfection (12)(13)(14).…”

Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma

“…We demonstrated efficacy and safety of Ad expressing the wild-type p53 gene (Ad-p53) to esophageal carcinoma at a preclinical level and in a phase I/II clinical study. 2,3 These studies indicated that transduction of esophageal carcinoma with an apoptosis-inducing gene was a possible therapeutic strategy.…”