| Text: At present, lung cancer is the leading cause of cancer death and non small-cell lung cancer (NSCLC) accounts for nearly 80% of all lung carcinoma. Most NSCLC cases have come in advanced stage until the final diagnosis and accordingly submitted to chemotherapy. The current received first-line chemotherapy protocols are cisplatin or carboplatin combined other cytotoxic drugs and however the general therapeutic effects are not ideal. P53 is an important tumor suppressor gene and play a significant role in tumorigenesis and development. P53 alteration occurs in 45%～75% of NSCLC. This article was aimed to investigate the relationship of p53 expression with chemosensitivity of NSCLC patients to platinum, the best time sequence in inhibitive effects of exogenous p53 combined DDP on NSCLC cells, and the mechanisms of sensitivity of NSCLC cells to cisplatin enhanced by p53 gene.Referring to the literatures about the significance of p53 alterations in patients with NSCLC on chemosensitivity to platinum, we recorded the relevant results and made quantitative assessment on the data with Meta analysis methods. Sixteen trials involving 1070 patients were retrieved. Among these, 539 patients (50.4%) were positive for p53 and the response rates to platinum were 33%; 531 patients were negative and the response rates were 44.4%; overall response rates to platinum were 38.7%. The combined OR was 1.37, with 95% confidence interval of 0.84-2.24. The results indicate the p53-negative patients are more sensitive to platinum than the p53-positive ones which however cannot be confirmed with statistical significance by current research.With MTT detection, to investigate the Inhibition of rAd-p53 combined with DDP in different time sequence on human lung adenocarcinoma cell lines A549, GLC-82 and lung large cell carcinoma cell lines 95D. Results showed that rAd-p53 can significant inhibit the three kinds of lung cancer cell lines growth in vitro. With the dose less than IC20, rAd-p53 combined with DDP showed a notable synergistic effect whose inhibition ratio of the combination of these both was significantly higher than single drug in same dose individually in different time sequence. The synergistic effects occurred regardless with drug administration sequence, but the best one took place in sequence of rAd-p53 administered at 48h before DDP.After lung cancer cells were treated with rAd-p53, Cell cycle and apoptosis was detected by flow cytometry and change of genes was identified by microarray. Results showed that combination of rAd-p53 and DDP obviously decreased proliferative cells and increased apoptosis cells compared with DDP alone. Its mechanism is related with p53 gene up-regulation which then induced many genes regulating cell cycle, proliferation and apoptosis to express up or down, for example CDKN1A,FAS,BAK1,TP53I3, TNFSF14, BTG2, MAD2L1,CCND1 etc.In a word, the p53-negative patients are possibly more sensitive to platinum than the p53-positive ones, but data come from literatures cannot confirm the relationship between p53 status of NSCLC patients and response rate to platinum. RAd-p53 combined with platinum exhibits synergistic inhibitory effects on all three kinds of tumor cell lines in vitro. The best synergistic effects take place in sequence of rAd-p53 administered 48h before DDP. Following introduction of rAd-p53, many genes regulating cell cycle, proliferation and apoptosis expresses up or down which significantly enhance chemosensitivity and killing efficiency of platinum on NSCLC cells. |
