| BACKGROUND AND OBJECTIVESmall-cell lung cancer (SCLC) accounts for about15%of all lung cancer and has poor prognosis, with5-year survival at diagnosis rarely exceeding15%. The survival of patients with SCLC has improved only marginally in the past25years. Most patients with SCLC show relapse and die because of the disease despite achieving high response rates with combination first-line therapy; the prognosis is especially poor with chemotherapy resistance to first-line treatment.Although etoposide plus cisplatin (EP) regimen has been the mainstay of ED-SCLC treatment, median overall survival is about9months, with5to10%surviving2years and only1%of patients achieving long-term disease-free survival. Although various attempts have been made improve this outcome further, which included dose intensity with cytokines supports, maintenance therapy, and also searches for a better chemotherapy regimen, there is no consistent evidence of increasing in response rate or survival.Recent scientific investigations have identified the active chemical compounds in green tea as tea polyphones or catechins. A number of epidemiologic studies have linked the consumption of green tea to decreased risk of cancer. Animal models have supported the ability of green tea to prevent tumorigenesis. The most abundant catechin in green tea,(-)-epigallocatechin-3-gallate (EGCG), has shown strong anti-proliferative and anti-tumor effects in vitro and in vivo. A recent investigation of the effects of EGCG on human SCLC cells revealed EGCG with similar anti-tumor effects on drug-sensitive (H69) and drug-resistant (H69VP) SCLC cells.STUDY CONTENTS1Identification growth inhibition to SCLC of EGCG.2Flow cytometry for cell cycle analysis with EGCG, DDP or both.3Flow cytometry for determining early apoptosis with EGCG, DDP or both.4Phase I trial has been carried out to investigate safety of (-)-epigallocatechin-3-gallate, time of progression free survival and change of serum markers in small-cell lung cancer patients.METHODS AND RESULTS1EGCG and DDP inhibit cell proliferation in SCLC. We examined the effects of increasing concentrations of EGCG for different times on the growth of H446cells. EGCG displayed cytotoxic properties:the IC50for EGCG was254±11,160±9, and114±10μM for24,48,72h, respectively, and that for DDP was3±0.15,1.98±0.1, and1.32±0.1μg/ml, respectively. We chose the concentrations of80and160EGCG and1μg/ml DDP and the incubation time of48h for further experiments. Cell viability was reduced with concentrations of EGCG with or without DDP.2Combination therapy induced cell cycle arrest at the G2/M phase. To further understand the mechanics underlying the reduced viability with different concentrations of EGCG with or without CDDP, we used flow cytometry of H446cells. EGCG (80or160μM) did not alter cells in the G2/M phase; however, combined treatment with CDDP caused substantial accumulation of cells in the G2/M phase; furthermore, co-treatment with EGCG (80μM) increased the proportion of cells in the G2/M phase as compared with CDDP treatment alone (p<0.05).3EGCG augments early apoptosis as detected by Annexin V-FITC/PI staining. To confirm further the apoptotic model of cell death, we performed Annexin V-FITC/PI staining and flow cytometry after treatments for48h. Treatment with EGCG, CDDP, and their combination significantly increased early apoptosis staining as compared with control treatment. Furthermore, early apoptosis induced by combination treatment of CDDP with EGCG (80or160μM) was significantly higher than with CDDP alone. 4Adopt traditional3+3design and dose escalation method of modified Fibonacci as maintenance therapy for extensive-stage Small Cell Lung Cancer. To date, there are11patients were enrolled onto the study, no patient experienced a dose limit toxicity, the median disease free survival has not achieve, the change of serum markers, neuron specific enolase and carcinoma embryonic antigen before and1month after using EGCG with no difference. |
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