Spotlight on bevacizumab and its potential in the treatment of malignant pleural mesothelioma: the evidence to date.

Malignant pleural mesothelioma (MPM) is a rare, but aggressive cancer. Surgery and radiation offer limited benefit, and systemic chemotherapy remains the primary treatment modality for the majority of patients. Vascular endothelial growth factor (VEGF) and its receptor have been recognized as important players in the biology of this disease. Bevacizumab is a monoclonal antibody that binds VEGF and blocks its interaction with the VEGF receptor. Recent studies have shown benefit with the addition of bevacizumab to the combination of cisplatin and pemetrexed in MPM. This combination is now included in the National Comprehensive Cancer Network guidelines (with a category 2A recommendation) as a possible first-line treatment for unresectable MPM in appropriately selected patients. This review discusses the rationale behind the use of bevacizumab in MPM, as well as summarizes the pharmacology, efficacy, safety, and toxicity of bevacizumab across multiple trials. The use of small-molecule inhibitors of angiogenesis in the treatment of MPM is also discussed.

Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells.

PURPOSE: Nuclear factor kappaB (NFkappaB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFkappaB activity may be prognostic, and inhibition of NFkappaB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFkappaB activity and the effects of inhibiting NFkappaB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine. EXPERIMENTAL DESIGN: The gemcitabine sensitivity of pancreatic cancer cell lines BxPC-3, L3.6pl, CFPAC-1, MPanc-96, PANC-1, and MIA PaCa-2 were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting assays. NFkappaB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFkappaB activity were determined in vitro and in vivo. NFkappaB was inhibited by silencing of the p65/relA subunit using small interfering RNA in vitro and by neutral liposomal delivery of small interfering RNA in vivo, and the effects were evaluated on gemcitabine sensitivity. RESULTS: The cell lines L3.6pl, BxPC-3, and CFPAC-1 were sensitive, whereas MPanc-96, PANC-1, and MIA PaCa-2 were resistant to gemcitabine. No significant correlation was observed between basal NFkappaB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFkappaB either in vitro or in vivo. Silencing of p65/relA induced apoptosis and increased gemcitabine killing of all gemcitabine-sensitive pancreatic cancer cells. No significant effects, however, were observed on gemcitabine-resistant pancreatic cancer cell lines either in vitro or in vivo. CONCLUSIONS: NFkappaB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFkappaB may be a useful therapeutic target for a subset of pancreatic cancers.