Invited Commentary

Abstract

Treatment of non–small cell lung cancer (NSCLC) poses a challenge to oncologists as the prognosis for most patients with this disease remains poor. In the last decade, the paradigm of treating NSCLC with chemotherapy has shifted from that of nihilism to that of enthusiasm. Randomized clinical trials have demonstrated improvement of survival and quality of life among patients with advanced NSCLC treated with cisplatin-based chemotherapy versus supportive care alone. A plethora of new chemotherapeutic agents, such as gemcitabine HCl, paclitaxel, docetaxel, and vinorelbine tartrate, have also been introduced for treating NSCLC. However, measurable response rates of NSCLC to the modern regimens, for example, paclitaxel/carboplatin, are still in the range of 20% to 30% as demonstrated in randomized clinical trials. It is clear that NSCLCs are relatively chemoresistant (or chemoinsensitive) and that better systemic therapy must be developed for this devastating disease. One promising approach for systemic treatment of lung cancer is molecularly targeted therapy based on the knowledge of molecular biology of a particular tumor type. This approach is successful in introducing novel treatments other than the “traditional chemotherapy” for other tumor types. For example, trastuzumab, a monoclonal antibody targeting the HER-2/neu receptor is being used for breast cancer, and all-trans-retinoic acid, targeting the defective expression of the PML/RAR-α genes as a result of translocation of chromosomes 15 and 17, is being used for promyelocytic leukemia. It is believed that molecular targeting therapy for lung cancer is on the horizon as we better understand the molecular biology of lung cancer such as that reported in the article by Jones and associates. These authors showed that gemcitabine HCl in NSCLC cell lines upregulated the nuclear translocation of a transcription factor, nuclear factor-Kappa B (NF-κB), which is known for inhibiting programmed cell death or apoptosis. Furthermore, inhibition of the function of NF-κB by a repressor protein, IκBα-SR, led to an increase in chemosensitivity to gemcitabine HCl and in apoptosis. Thus, NF-κB and/or IκBα may be potential molecular targets for drug development. The future paradigm for systemic treatment for lung cancer will rest on the successful development of molecularly targeted therapy. Clinical trials are currently underway to investigate a number of target-specific agents such as inhibitors of protein kinases essential for cell cycle regulation, and inhibitors of metalloproteinases and cell surface receptors essential for angiogenesis and metastasis.