Clinical Research Of Acitretin On Differentiation Of Patients With Non-small Cell Lung Cancer

Background According to statistics, the incidence of lung cancer around the world is increasing at an annual rate of 0.5%, which brings about 600,000 new cases each year. In China, the incidence of lung cancer rose by 11% yearly in nearly 20 years.The total prevalence rate reached 20.41/10 million in 1990s. Non-small cell lung cancer (NSCLC) accounts 75% to 80% among all types of lung cancer. Patients with NSCLC diagnosed based on symptoms and pathology methods that are not very effective in early NSCLC detective, coupled with the cancer's poor sensitivity to radiotherapy and chemotherapy, current treatment of patients with NSCLC is not ideal, The 5-year survival rate of NSCLC patients received treatment is only 8 % -12% . Combined therapy, surgery,radiotherapy,chemotherapy, clinical treatment have been constituted three classical models in clinical. Increasing attention has been paid to biological treatment recently, and gradually developed into the fourth mode of treatment of lung cancer. Abnormal differentiation and apoptosis is blocked the main reason for the development of tumors ,accordingly induce tumor cell differentiation and apoptosis has become a hot spot of tumor treatment. Retinoic acid induced differentiation of acute promyelocyte leukemia (APL) has become the clinical treatment of hematologic malignancies conventional means.Retinoic acid has a variety of solid tumor cells induced differentiation, inhibit proliferation and induce apoptosis. Firstly,in view of differentiation inducer and traditional chemotherapy drugs through different mechanisms to the tumor cells.Secondly NSCLC cell heterogeneity own existence, resistance and individual difference factors, combined with previous studies conducted in our laboratory.Finally, from the cell morphology index and cell cycle kinetics can be found in retinoic acid induced differentiation of the treatment of advanced NSCLC patients and a tendency to improve their clinical efficacy, this research will continue to be Acitretin in treatment of advanced non-small cell lung cancer patients, and on the basis of previous studies adjust the treatment program, prolonged follow-up time, and cell differentiation-related gene from lung cancer resistance protein and further understanding of the different indicators of retinoic acid on the clinical efficacy of lung cancer patients, the clinical treatment of lung cancer to explore new ways to provide research basis.Objective Through using Acitretin for the treatment of advanced non-small cell lung cancer, to understand the changes of retinoic acid on morphology, cell cycle, hemodynamics, cyclin D1, cell cycle control protein (pRb), lung resistance protein LRP, peripheral blood tumor markers CEA, EGFR, CYFRA21-1, and NSE before and after treatment, and make clinical observation.Methods A treatment group and control group received 3 kinds of programs chemotherapy GP, NP, DP. Treatment group A(each 1 day after chemotherapy) and treatment B, Acitretin given 1 mg / (kg ? d), one course of treatment contained 7 days.Interval 14 days-re-use (and Chemotherapy synchronization). After 4 cycles of treatment assess the efficacy and toxicity. HE staining was observed under microscope before and after treatment of patients in treatment group, including morphological changes of cancer of plasma cells in the nuclear ratio, and thickness of cell membrane integrity- Using flow cytometry to assess A combination therapy treatment of malignant pleural effusion of lung B cells in groups of cells exfoliated cycle and DNA content; double antibody sandwich enzyme-linked immunosorbent assay (ELISA) for blood test Cyclin D1 (Cyclin D1), cell cycle control protein (pRb), epidermal growth factor receptor (EGFR), lung resistance-related protein ( LRP) and the electrochemilu- minescence immunoassay (ECLI) measured leukemia antigen (CEA), non-small-cell associated antigen (CYFRA21-1), neural specific enolase (NSE) levels and other changes before and after treatment.Results1. Acitretin conventional sequential treatment with four cycles of platinum chemotherapy, the treatment A group and B group treated lung cancer cells showed the morphology of lung cancer cells to differentiate into mature cells: the performance of the cell (relative) becames flat, the cell volume increased, nuclear shape structured nuclear / pulp ratio decreases; cytoplasm density reduced, nuclear became larger, nuclear density also reduced, intercellular widened, and appeared polarity.2. For patients with malignant pleural effusion in treatment A and B group after four cycles of treatment ,their serum levels of cell cycle factors CyclinD1 significantly lower than before, the difference was statistically significant (P <0.01), Treatment A and B group in serum levels of cell cycle control protein pRb increased than before (P <0.01). Flow cytometric analysis of pulmonary malignant pleural effusion cytology showed that-the proportion of G0/G1 phase of treatment A group and treatment group B increased(P<0.05) , while S phase, G2 / M phase decreased significantly compared with before (P < 0.05)..3.165 patients with serum markers of tumor markers were higher than normal levels after treatment of four cycles of treatment A group, treatment group and control group B (P <0.01), and the treatment A group decline was significantly obvious than other groups (P <0.01). Lung resistance-related protein(LRP) expression levels in treatment group A and treatment group B was lower than before treatment, and significant difference was found (P <0.01). LRP levels than before treatment was significantly higher (P <0.01). Acitretin combined with chemotherapy sequential therapy group, serum indexes of lung cancer resistance protein (LRP) decreased significantly than chemotherapy alone, indicating that retinoic acid has reduced the degree of malignancy of lung cancer cells, While increased sensitivity to chemotherapeutic drugs effect. 4.The clinical efficacy (CR + PR)% and disease control rate (CR + PR + SD)% of the treatment A group is 57.33% and 94.67% respectively. Which higher than that of the treatment group and control group B. Clinical efficiency and disease control rate among three groups have statistically significant differences (P <0.05). COX regression model suggests that ways of treatment may affect the prognosis,Since age did not enter the COX regression model, suggesting that the age may not related to prognosis of non-small cell lung cancer .5.Differences of side effects such as skin lesions of treatment A and B group before and after treatment was significantly (P <0.05). Liver and kidney functions in the treatment group and control group A have different degrees of damage before and after treatment (P <0.05). While found no differences in treatment B group.Conclusion Acitretin sequential therapy combined with platinum chemotherapy for advanced non-small cell lung cancer patients after four cycles, we found that retinoic acid can induce cancer cell differentiation, cell cycle arrest and reduce the degree of malignancy of lung cancer cells, synergistic increase the efficacy of chemotherapy.It found that changes of the cell morphology, cell cycle kinetics, cell cycle related protein, lung resistance protein and serum levels of tumor before and after treatment from indexes of blood cancer,chemotherapy resistance and clinical aspects of disease control rate,compared with chemotherapy alone, we also found that sequential Acitretin combined with chemotherapy treatment increase the effect of treatment ,while has mild side effects.In conclusion,it has a certain clinical significance in improving the clinical efficacy and survival of advanced non-small cell lung cancer .