ObjectiveTo study effects of two kinds of epidermal growth factor receptor kinase inhibitors on bleomycin-induced pulmonary fibrosis in mice, and regulation mechanism on oncostatin M (OSM) and downstream signaling pathways.MethodsForty Kunming female mice were randomly divided into a control group, a fibrosis group, a gefitinib group, and an erlotinib group. The mice in the control group were administered with saline aerosol intratracheally. The mice in the fibrosis group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally. The mice in the gefitinib group and the erlotinib group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally and then gastrically perfused with gefitinib (20 mg·kg–1·d–1) or erlotinib (25 mg·kg–1·d–1). All mice accepted computer tomography examination 14 days after the treatment and then were sacrificed, and the lungs were collected for further detection. The lungs were stained with hematoxylin eosin and Masson’s trichrome, examined with Western blot for pathological examination and expressions of α-smooth muscle actin (α-SMA), OSM, Janus kinase 1 (JAK1), phospho-JAK1 (p-JAK1), signal transducers and activators of transcription 3 (STAT3), and phospho-STAT3 (p-STAT3) proteins.ResultsThe pathological injury of the lung in the gefitinib group and the erlotinib group was significantly relieved compared with that in the bleomycin group. The expressions of α-SMA, OSM, p-JAK1/JAK1, and p-STAT3/STAT3 proteins were also significantly reduced. There were no differences between the above-mentioned indexes between the gefitinib group and the erlotinib group.ConclusionsGefitinib and erlotinib can significantly relieve bleomycin-induced pulmonary fibrosis in mice. The underlying mechanism may be involved in inhibiting expression of OSM and downstream JAK/STAT pathways.
Objective To evaluate the efficacy of Gefitinib for patients with non-small-cell lung cancer (NSCLC). Methods We searched several databases, including MEDLINE (1991 to June 2008), The Cochrane Library (Issue 4, 2008) and CBMDisc (1978 to Feb. 2008). Randomized controlled trials (RCTs) were included in the meta-analyses, which were done using The Cochrane Collaboration’s RevMan 4.2 software. We also included retrospective case reports published in Chinese journals. Results Eight RCTs and 36 uncontrolled case reports were analyzed. The results of the RCTs showed that 250 mg/d Gefitinib had similar efficacy to 500 mg/d, but the side effect was significantly less for the lower dose. When used as a combined first-line treatment or a third-line treatment, Gefitinib was not superior to placebo on response rate, survival rate and life span. When used as second-line treatment, it did not prolong median survival, though it gave a higher response rate than placebo. Gefitinib caused many more side effects than placebo. Gefitinib exhibited similar efficacy to docetaxel in objective response rate [OR 1.18, 95%CI (0.84, 1.67), P=0.35], but was better for symptom and quality-of-life improvement [OR 1.58, 95%CI (1.33, 1.89), Plt;0.00001]. The overall uncontrolled clinical studies showed the following results: complete response rate was 2.2%, partial response rate was 25.8%, disease stable rate was 40.0% and progressive disease rate was 32.0%. The average median survival time was 8.9 months; the average time to progressive disease was 5.2 months, and the 1-year survival rate was 44.2%. The average median survival from EAP studies (6.9 months) was shorter than that for all the studies as well as the registered clinical trials (10.0 months). The average periods to progressive disease for registered clinical trials (3.2 months) and EAP studies (4.4 months) were somewhat shorter than that found for all studies combined, though response rate and 1-year survival rate were similar. Since there was no controlled clinical study, it was hard to conclude from the results whether Gefitinib brought any clinical benefit to NSCLC patients in China. Conclusion Gifitinib is not suitable as a combined first-line treatment or a third-line treatment for NSCLC. The clinical favor from gefitinib in the second-line treatment remains uncertain. There is not enough evidence to show whether Chinese people are more sensitive to Gefitinib, and its use in the second-line treatment of NSCLC needs to be tested further.
Objective To investigate the effects of gefitinib in the treatment of sarcomatoid carcinoma. Methods Clinical data of a case of sarcomatoid carcinoma was analyzed and related literatures were reviewed.Results A patient with sarcomatoid carcinoma was admitted with progressive dry cough,chest pain and dyspnea for 3 months. The patient was diagnosed as lung sarcomatoid carcinoma by thoracoscopy and treated with gefitinib. After 2 weeks treatment, symptoms disappeared and tumor was stable for 4 months. Literatures review suggested that sarcomatoid carcinoma is a rare malignant tumor. Treatment of sarcomatoid carcinoma includes surgery, chemotherapy and radiotherapy, but these methods show little effect in advanced patients. In our case, the patient with sarcomatoid carcinoma in stage Ⅳ was treated by gefitinib and showed favourable effect. Conclusions Advanced sarcomatoid carcinoma patients have a short life span and poor life quality. Gefitinib may provide these patients a feasible therapeutic approach.
Objective To investigate the feasibility of detection of epidermal growth factor receptor ( EGFR) exon 19 deletions and exon 21 L858R mutations in pleural effusion fromnon-small-cell lung cancer ( NSCLC) patients by mutant enriched PCR assay. Methods The mutations of exon 19 and 21 of EGFR gene in pleural samples fromthirty NSCLC patients were analyzed using both the mutant-enriched PCR assay and the non-enriched PCR assay. Results Ten ( 33. 3% , 10/ 30) exon 19 deletions and five ( 16. 7% , 5/30) exon 21 L858R mutation were detected by the mutant-enriched PCR assay, while only 6 cases ( 20. 0% ) and 1 case ( 3. 3% ) were detected by the non-enriched PCR assay respectively. The difference of mutation detection rate of EGFR gene between the two methods was statistically significant ( P = 0. 032) . Mutations were detected in all of partial responders ( 2 /4) among the four patients who received gefitinib therapy. Conclusions Mutant-enriched PCR assay can detect EGFR exon 19 deletions and exon 21 L858R mutation in pleural effusion from NSCLC patients effectively, economically and accurately. It may be a valuable biomarker for gefitinib therapy in advanced NSCLC.
Objective To observe the effect of gefitinib on expression of epidermal growth factor receptor (EGFR) in bile duct epithelial cells, and the feasibility of inhibiting hyperplasia of bile duct epithelial cells with gefitinib. Methods Sixty-one patients with hepatolithiasis having to be in hospital for surgery from the First People’s Hospital of Shuangliu county were selected, with 25-65 years old, average 46.92 years. The patients were randomly divided into therapy group and control group. There were 30 cases in therapy group, in which fine duct was placed on lesion bile duct during operation, and through whom gefitinib solution was perfused after operation. There were 31 cases in control group with only T tube drainage after operation. The bile duct sample was obtained respectively during the operation and 6 weeks and 12 weeks after operation. The histology and expression change of EGFR were observed by HE staining, immunohistochemistry and RT-PCR method respectively. Results There were no significant differences in pathohistology changes of bile duct and the EGFR protein and mRNA expression between therapy group and control group during operation. The hyperplasia of epithelium mucosae and submucosal gland in the therapy group were obviously decreased as compared with those in control group, the EGFR mRNA and protein expression in therapy group were weaker than those of control group （Plt;0.05） 6 weeks and 12 weeks after gefitinib treatment. Conclusion EGFR is overexpressed in the chronic proliferative cholangitis, and continuously local application of gefitinib after operation can specifically interrupt the activation and expression of EFGR and then effectively inhibit the hyperplasia of bile duct epithelial cells.
【摘要】 目的 评估吉非替尼治疗终末期（PS评分≥3分）非小细胞肺癌（NSCLC）的临床效果和生活质量改善情况。 方法 2008年5月-2010年6月共收治终末期NSCLC患者40例，其中19例患者采用吉非替尼治疗（治疗组），21例采用支持治疗+中药治疗（对照组）。 结果 治疗6个月后，治疗组19例患者中，CR 1例，PR 5例，SD 10例，PD 3例。治疗组有效率为31.5%（6/19），临床受益率为84.2%（16/19）。对照组21例中，SD 5例，PD 16例，无CR。对照组有效率为23.8%（5/21），临床受益率为 23.8%（5/21）。两组间有效率和临床受益率比较，差异均有统计学意义（Plt;0.05）。治疗组中位生存期为13.2个月，对照组中位生存期为4.5个月。 结论 吉非替尼可延长NSCLC患者的生存期，改善其生活质量。【Abstract】 Objective To evaluate the curative effect and life improvement of gefitinib on non-small cell lung cancer (NSCLC) which in the end stage. Methods Forty patients with end-stage NSCLC were treated from May 2008 to June 2010. Nineteen patients of them were treated with gefitinib (treatment group), 21 patients were treated with supportive care and traditional Chinese medicine treatment (control group). Results Six months after treatment, there are one patient with CR, five patients with PR, 10 patients with SD and three patients with PD in the treatment group. The effective rate of treatment group was 31.5% (6/19), clinical benefit rate was 84.2% (16/19). There are five patients with SD, 16 patients with PD, and no one with CR in the control group. The effective rate of the control group was 23.8% (5/21), clinical benefit rate was 23.8% (5/21). The differences of effective rate and clinical benefit rate between two groups were statistically significant (Plt;0.05). The median survival period of the treatment group and control group were 13.2 and 4.5 months respectively. Conclusion Gefitinib can extend the lifetime of NSCLC patients and improve their quality of life.
Objective To evaluate the effects of two different epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs) , Gefitinib and Erlotinib, on lung fibrosis induced by bleomycin.Methods Forty BALB/c female mice were randomly divided into four groups, ie. a control group( saline given orally and intratracheally) , a fibrosis group( saline given orally with bleomycin instillation) , a Gefitnib group( Gefitnib 20 mg/kg given orally with bleomycin instillation) , and an Erlotinib group ( Erlotinib25 mg/kg given orally with bleomycin instillation) . Bleomycin ( 3 mg/kg) was intratracheally instilled on the first day. Gefitinib or Erlotinib was given orally daily and normal saline as control. Then they were sacrificed by abdominal aortic bleeding 14 days after the bleomycin instillation. The left lung was stained with HE and Masson’s trichrome staining respectively for pathological examination. Total EGFR and phosphorylated EGFR were detected by immunohistochemistry. Hydroxyproline ( HYP) assay was performed in the right lung.Results Both Gefitinib and Erlotinib significantly reduced lung collagen accumulation and the content of HYP. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited. Furthermore, there was no difference between Gefitinib and Erlotinib in inhibiting lung fibrosis. Conclusion Our findings suggest that, in the preclinical setting, EGFR-TKIs may have aprotective effect on lung fibrosis induced by bleomycin.
Objective To evaluate the safety and efficacy of gefitinib in comparison with platinum-based doublets chemotherapy as a first-line precision treatment for advanced non-small cell lung cancer (NSCLC), and find the benefit population of gefitinib. Methods The Cochrane Library, PubMed, Embase, China National Knowledge Internet, VIP database and China Biology Medicine database were searched to collect the randomized contolled trials (RCTs) of gefitinib vs. platinum-based doublets chemotherapy for advanced NSCLC from inception to November, 2017. The data in the included RCTs were extracted, and the qualities were assessed in accordance with Cochrane Collaboration, and a Meta-analysis was conducted with RevMan 5.3 software. Results Four trials were included, including 968 subjects in the gefitinib group and 968 subjects in the chemotherapy group, and a majority of the subjects were diagnosed advanced adenocarcinoma, and all of the subjects were East Asians. The results of Meta-analysis showed that in all population or patients with epidermal growth factor receptor (EGFR) mutation-positive, gefitinib was better than chemotherapy in progression-free survival (PFS) [in all population: hazard ratio (HR)=0.76, 95% confidence interval (CI) (0.67, 0.85), P<0.000 01; in patients withEGFR mutation-positive: HR=0.42, 95%CI (0.35, 0.50), P<0.000 01] and objective response rate (ORR) [in all population: risk ratio (RR)=1.30, 95%CI (1.15, 1.47), P<0.000 1; in patients withEGFR mutation-positive: RR=1.92, 95%CI (1.46, 2.52), P<0.000 01], and there was no significant difference between the two groups in overall survival (OS) (P>0.05); but inEGFR mutation-negative, chemotherapy was better than gefitinib in PFS [HR=2.09, 95%CI (1.05, 4.13), P=0.03]. Subgroup analysis showed that in female patients, for patients with Performance Status (PS) score 0 or 1, and the ones who never smoked, gefitinib was better than chemotherapy in PFS (P<0.05); but there was no significant difference between the two groups in OS (P>0.05). The incidences of rash, itching, dry skin, paronychia, diarrhea, aminotransferase abnormality were higher in the gefitinib group (P<0.05), while the incidences of hair loss, vomiting, nausea, constipation, anorexia, leukopenia, thrombocytopenia, and neutropenia, anemia, fatigue, nerve toxicity reaction were higher in the chemotherapy group (P<0.05). Conclutions Based on the current evidence, in patients with adenocarcinoma of East Asians, the benefit population are those with the characteristics of EGFR mutation-positive, female, never smoking, and PS 0 or 1. In the aspect of safety, the common adverse drug events in subjects treated with gefitinib are the damage of skin mucous membrane, but the incidences of digestive system diseases and the blood system diseases are less in patients treated with gefitinib than those with chemotherapy.