NF-KB : SECOND-LINE TREATMENT FOR SMALL CELL LUNG CANCER

Nuclear factor kappa light chain of B cells enhanced activation (NF - KB), through Is the central mediator of immune response (197). Track Caused by various stimuli in many of the tumor microenvironment, and There are hundreds of active particles downstream (198). Five NF - KB protein DNA is inhibited to link all the copies and the organization and activity by the NF - KB IKB. When specific residues Serine phosphorylated IKB, IKB aims to
Degradation of the proteasome (199). Family IKB kinase (IKK) and five members (200). In response to stimulation, a procedure of this family is phosphorylate IKB, leading to collapse. A variety of factors aimed IKK family In various stages of development. And CHS828 SU6668, and two molecules Under evaluation in clinical trials early. Who is the proteasome
Multisubunit protein, its role is the destruction of proteins (201). And proteasome ubiquinated degrade many different proteins. The work of anti-tumor It is supposed to disturb proteasome destruction of IKB, which is the highest IKB lead to greater levels of inhibition of NF - KB.
There are many factors evaluated clinically for inhibition of NF - KB Considered one of the mechanisms of action. Bortezomib is the only factor Comprehensive assessment of lung cancer, which is the inhibition of NF - KB The main mechanism of action. Bortezomib is the first approved by the Food and Drug Administration proteasome Inhibitor. It is a modified boronic dipeptidyl acid, which prevents reverse Chymotrypsin like activity of proteasome 26S. The FDA approved drug bortezomib On May 13, 2003 for patients with multiple myeloma (202). In December 2006, Has been extended to the approval of bortezomib for patients with mantle cell (203). Bortezomib has been evaluated extensively in solid tumors. After The Undersecretary of the single dose of bortezomib has been evaluated in combination
With first-line chemotherapy for NSCLC, second-line treatment for NSCLC And second-line treatment for small cell lung cancer. Having examined the first phase of studies bortezomib in combination with gemcitabine and carboplatin (204) and in conjunction Gemcitabine and cisplatin (205). Bortezomib mg/m2 1,0 on days 1, 4 and 8 And 11 plus gemcitabine 1000 mg/m2 on days 1 and 8, 5.0, carboplatin AUC Found on the first day of a cycle of 21 days is safe. Bortezomib mg/m2 1,0 on days 1 and 8 plus gemcitabine 1000 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 Day 1 Was also considered in a cycle of 21 days is safe. Due to gastrointestinal toxicity and Myelosuppression, the pace of bortezomib lower in cisplatin
The study. Phase II study assessing bortezomib and gemcitabine in association with
Carboplatin doses higher than previously untreated patients with NSCLC. The average overall survival was 11 months and progress-free survival was 5 and Months. The bloody events in the negative the first place. Was a very good program Tolerance, but the survival of public life and survival progression-free and similar to Historical data (206). There are three approved second-line treatment of NSCLC, docetaxel (207, 208), Pemetrexed (209) and erlotinib (210). Were evaluated in three in combination with bortezomib. Having studied and Bortezomib docetaxel in several studies (211 212). Phase I study evaluated 36 patients with NSCLC in most cases. Two patients Achieved a partial response and seven achieved stable disease. Recommended Phase II dose of 1,0 bortezomib mg/m2 on days 1, 4, 8 and 11 in combination with docetaxel 75 mg/m2 day 1 every 21 days. In a randomized Phase II of 155 patients 1,5 mg/m2 bortezomib compared with 1,3 bortezomib mg/m2 and docetaxel 75 mg/m2 day 1. The sessions of the treatment 21 days, and bortezomib was given for Days 1, 4, 8 and 11. The response rate was 8%, with rates of control of disease progression by 29% The bortezomib alone, and a response rate of 9% of the rate of disease control 54% of the combined treatment arm. Bortezomib was evaluated pemetrexed In the first phase of clinical trials (213). Responses were observed, the dose recommended by the Phase II Pemetrexed was 500 days, and bortezomib 1,3 mg/m2 1 mg/m2 days 1, 4, 8 and 11 Cycle of 21 days. Bortezomib mg/m2 1,6 on days 1 and 8 of a cycle of 21 days and Were compared erlotinib 150 mg orally with erlotinib alone in the second phase randomized clinical trials Study (214). Despite the fact that combination therapy is well tolerated, and the study Stopped after 50 patients were treated after the planned interim analysis Demonstrate sufficient clinical activity in the combination arm. Small cell lung cancer relapse following is a difficult clinical scenario. Bortezomib Was evaluated only for the treatment of small cell lung cancer (215). Was recorded thirty-six patients in the Phase II study of bortezomib in Only in patients who were treated before with 1,3 mg/m2 intravenously on days 1, 4, 8 and 11 every 21 days. Average survival progression-free and overall survival And 1 and 3 months, respectively, and there is no clear answer. These results Is sufficient to move forward in the development of bortezomib on Clinical situation. Although many of the clinical data generated to evaluate bortezomib Lung cancer is currently no data demonstrating the role of the agent Treatment of lung cancer. It was noted that the reactions even in the script alone, But these reactions are rare. There is no convincing evidence that In addition to standard treatment bortezomib improves the outcome. It is still possible And can be detected for these differences in an atmosphere of studies, either by selecting Subset of patients who suffer from high possibility of response to bortezomib. And Likely that other inhibitors of the proteasome in progress to create More effective.