Gene therapy for lung cancer. An introduction.

Incremental progress will likely continue to be made in the treatment of lung cancer using the conventional treatment modalities. However, there is now hope that the development of noncross-resistant modalities that can be accomplished using the technology of gene transfer may hasten the progress made in this disease. Although significant progress has been made, the practical application of the various strategies to the treatment of cancer patients in clinical trials has yielded only very limited results.

Management of advanced non-small cell lung cancer: current trends.

Carcinoma of the lung continues to be the leading cause of cancer-related deaths for Americans. Major efforts have been made in the treatment of advanced non-small cell lung cancer; chemotherapy and investigations in the last decade have yielded a number of new agents and combinations. Despite progress with newer agents for the treatment of non-small cell lung cancer, only 14% of patients with the disease are alive 5 years after the initial diagnosis.

Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.

Non-receptor and receptor tyrosine kinases, such as Src and EGF receptor (EGFR), are major inducers of vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis. While tyrosine kinases signal through multiple pathways, signal transducer and activation of transcription 3 (Stat3) is a point of convergence for many of these and is constitutively activated with high frequency in a wide range of cancer cells. Here, we show that VEGF expression correlates with Stat3 activity in diverse human cancer cell lines.

Direct repression of the Mcl-1 promoter by E2F1.

E2F1 induces apoptosis via both p53-dependent and p53-independent mechanisms. The direct targets in the p53-independent pathway remain enigmatic; however, the induction of this pathway does not require the transactivation domain of E2F1. Using cells that are defective in p53 activation, we show that E2F1 potently represses the expression of Mcl-1--an anti-apoptotic Bcl-2 family member whose depletion results in apoptosis.

Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation.

Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic signaling proteins that participates in normal cellular responses to cytokines and growth factors. Frequently, however, constitutive activation of certain STAT family members, particularly Stat3, has accompanied a wide variety of human malignancies. To identify small molecule inhibitors of Stat3, we investigated the ability of the Stat3 SH2 domain-binding peptide, PY*LKTK (where Y* represents phosphotyrosine), to disrupt Stat3 activity in vitro.

Treatment of advanced non-small-cell lung cancer: a review of current randomized clinical trials and an examination of emerging therapies.

Background: Lung cancer continues to be the leading cause of cancer-related deaths for Americans. As most patients present with nonsurgically curable disease, major efforts have been made in the treatment of advanced non-small-cell lung cancer (NSCLC) with chemotherapy. Several new agents and new combinations of chemotherapy are available.

Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability.

Our recent work has shown that activation of the Ras/Raf/ERK pathway extends the half-life of the Myc protein and thus enhances the accumulation of Myc activity. We have extended these observations by investigating two N-terminal phosphorylation sites in Myc, Thr 58 and Ser 62, which are known to be regulated by mitogen stimulation. We now show that the phosphorylation of these two residues is critical for determining the stability of Myc.