EFFECTS OF p53 GENE THERAPY COMBINED WITH CYCLOOXYGENASE-2 INHIBITOR ON CYCLOOXYGENASE-2 GENE EXPRESSION AND GROWTH INHIBITION OF HUMAN LUNG CANCER CELLS

Background Gene therapy by adenovirus-mediated wild-type p53 gene transfer has been shown to inhibit lung cancer growth in vitro, in animal models, and in human clinical trials. The antitumor effect of selective cyclooxygenase (COX)-2 inhibitors has been demonstrated in preclinical studies. However, no information is available on the effects of p53 gene therapy combined with selective COX-2 inhibitor on COX-2 gene expression and growth inhibition of human lung cancer cells. Methods We evaluated the effects of recombinant adenovirus-p53 (Ad-p53) gene therapy combined with selective COX-2 inhibitor on the proliferation, apoptosis, cell cycle arrest of human lung adenocarcinoma A549 cell line, and the effects of tumor suppressor exogenous wild type p53 on COX-2 gene expression. Results Ad-p53 gene therapy combined with selective COX-2 inhibitor celecoxib shows significant synergistic inhibition effects on the growth of human lung adenocarcinoma A549 cell line. Exogenous p53 gene can suppress COX-2 gene expression. Conclusions Significant synergistic inhibition effects of A549 cell line by the combined Ad-p53 and selective COX-2 inhibitor celecoxib may be achieved by enhancement of growth inhibition, apoptosis induction and suppression of COX-2 gene expression. This study provides first evidence that the administration of p53 gene therapy in combination with COX-2 inhibitors might be a new clinical strategy for the treatment or prevention of NSCLC.

Clinicopathological and Molecular Biological Studies of Primary Pulmonary Carcinoma with the p53 Gene Mutations

Objective To investigate the relationship between p53 aberrations and human pulmonary carcinoma prognosis and to evaluate as a genetic marker in the prognostic significance of the P53 mutations in the lung cancer. Methods DNAs from normal (n=5) and tumor (n=31) tissue specimens from non-small cell lung carcinomas (NSCLC), p53 exons 5-8 mutations were analyzed by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis. Results The detected mutation rate is 48.4％ (15/31) in the pulmonary carcinoma group, which was significantly higher than that in the control group. The control group showed that there is no p53 mutations. In the pulmonary carcinoma group, detection rates of p53 exons 5-8 mutations for squamous cell carcinomas, adenocarcinomas, bronchioloalveolar carcinomas and large cell carcinomas were 56.3％, 30.0％, 33.3％ and 100.0％, respectively. The incidence of p53 point mutational activation in the adenocarcinomas was lower in pulmonary carcinomas as compared to that in the squamous cell carcinomas. The level of p53 gene mutations was associated with TNM stages, the mutations of p53 gene in cancer tissues of the stages Ⅲ -Ⅳ were higher than in tumor stage Ⅰ and/or stage Ⅱ (χ2=6.556, P=0.038). The mutations in poor differentiated tumors were obviously higher than well differentiated and moderately differentiated tumors (χ2=4.045, P=0.044; χ2=4.232, P=0.040, respectively). However, statistical analysis showed that there is no significant correlations between p53 mutations and other clinical parameters, such as: age, sex, tumor size, and histological subtypes. Conclusion Detection of p53 gene mutations in lung carcinomas by PCR-SSCP can be used as a follow-up intermediate biomarker for the prognostic surveillance of human pulmonary carcinoma.

Efficacy of Recombinant Adenoviral Human p53Gene in Treatment of Malignant Pleural or Peritoneal Effusions