Adenovirus-mediated inhibitor kappaB gene transfer improves the chemosensitivity to anticancer drugs in human lung cancer in vitro and in vivo.

BACKGROUND: Nuclear factor kappaB (NFkappaB) is a transcription factor which is importantly implicated in cancer cell growth. In a previous report, we confirmed that lung cancer cell growth was suppressed significantly by the blockade of NFkappaB function. In this study the combination effect of chemotherapy and inhibition of NFkappaB on the human lung cancer cell line, NCI-H460, in vitro and in vivo was investigated. MATERIALS AND METHODS: In the in vitro experiment, 50% of cell growth inhibitory concentrations (IC50) of chemotherapy agents were determined alone or when combined with adenovirus mediated IkappaBalpha gene transfer. Annexin-V/PI stain and caspase 3 activity measurement were used to detect the apoptosis caused by treatment. In the in vivo experiment, the tumor growth suppressive effect of combination treatment was evaluated for tumor-bearing mice. NFkappaB, p53 and VEGF expression in the tumors were also analyzed immunohistologically. RESULTS: Several chemotherapy agents, including paclitaxel, showed lower IC50s when combined with AdIkappaBalpha infection in vitro. Apoptosis through activation of the caspase 3 pathway was enhanced by the combination treatment. For established NCI-H460 tumors, combined treatment significantly inhibited tumor growth. Immunohistochemical staining showed increased expression of p65 after paclitaxel treatment, while paclitaxel in combination with AdIkappaBalpha intratumoral injection eliminated this expression accompanied by the slightly reduced expression of VEGF, with stable p53 status. CONCLUSION: A combination of chemotherapy and IkappaBalpha could inhibit tumor growth effectively by blocking the expression of NFkappaB and inducing apoptosis. Moreover, it might allow reduction of the dose of chemotherapy agents and provide benefit for clinical application.

Immunohistochemical expression of MRP2 and clinical resistance to platinum-based chemotherapy in small cell lung cancer.

Determining an effective predictor of clinical drug resistance in small cell lung cancer (SCLC) is considered to be important. In this study, the relationship between the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and MRP2, which are the members of ATP-binding cassette superfamily transporter, and of the p53 tumor suppressor gene and the response to chemotherapy were analysed. The expression of P-gp, MRP1, MRP2, and p53 was determined by an immunohistochemical analysis of transbronchial biopsy (TBB) specimens from 61 SCLC patients. The relationship of such expression was also investigated regarding chemotherapy and clinicopathological factors. The response rate in the MRP2-negative group was significantly higher than that in the MRP2-positive group (88% versus 50%). The P-gp-negative group responded significantly better to chemotherapy than the P-gp-positive group, with a response rate of 81% versus 39%. No relationship could be found between the response to chemotherapy and immunostaining for MRP1 or p53. In 37 patients treated with platinum-based chemotherapy, the response rate of patients in the MRP2-negative group was significantly higher than that in the positive group (92% versus 50%). In a multiple logistic regression analysis, MRP2 as well as P-gp were shown to be statistically significant predictors of chemotherapy resistance. These results suggest that immunostaining of MRP2 for TBB specimens may help to predict clinical resistance to platinum agents. This is the first report which indicates that the immunohistochemical expression of MRP2 is positively related to a clinical resistance to platinum.