A phase II study of single-agent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer

The aim of this study was to evaluate the efficacy and tolerability of gefitinib ('IRESSA') in Japanese patients with previously untreated stage IV non-small-cell lung cancer (NSCLC). This was a multi-institutional phase II study. Thirty-four patients with previously untreated stage IV NSCLC were enrolled between May 2003 and September 2004. Gefitinib was administered orally 250 mg once a day and was continued until there was either disease progression or severe toxicity. Objective tumour response rate was 26.5% (95% confidence interval, 11.7-41.3%). Adverse events were generally mild (National Cancer Institute-Common Toxicity Criteria grade 1 or 2) and consisted mainly of skin rash, fatigue and liver dysfunction. No pulmonary toxicity was observed. The global health status revealed that there was no change in quality of life during the study. This study found that single-agent gefitinib is active and well tolerated in chemo-naive Japanese patients with advanced NSCLC.     

Novel heteroduplex method using small cytology specimens with a remarkably high success rate for analysing EGFR gene mutations with a significant correlation to gefitinib efficacy in non-small-cell lung cancer

We conducted a feasibility study to examine whether small numbers of cancer cells could be utilised for analysis of the EGFR gene status using the loop-hybrid mobility shift assay, which is a modified heteroduplex technique. Cytology specimens obtained by transbronchial abrasion were successfully used for analysis of the EGFR gene status in 50 of 52 (96.2%) patients diagnosed with class V non-small-cell carcinoma. Furthermore, the relationship between the EGFR gene status and clinical outcome was analysed in 25 patients treated with gefitinib. Overall, 10 of 11 patients with EGFR mutations in exon 19 or 21 showed tumour regression with gefitinib treatment, compared to only two of 14 patients with wild-type EGFR. The response rate was significantly higher in the EGFR mutation group than in the wild-type EGFR group (90.9 vs 14.3%, P=0.00014). Logistic regression analysis revealed that EGFR mutations in cytology specimens represented an independent predictor of the gefitinib response. The overall and progression-free survivals were significantly longer in the EGFR mutation group than in the wild-type EGFR group (P<0.05). In conclusion, cytology specimens could be useful for analysing the EGFR status in the majority of patients with non-small-cell lung cancer to determine whether they are likely to benefit from gefitinib treatment.     

Preclinical study of a "tailor-made" combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa) for disseminated peritoneal scirrhous gastric cancer

We evaluated the effect of a "tailor-made" chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailor-made approach, we first selected gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor)-sensitive SGC cell lines, and 5/8 cell lines demonstrated various degrees of gefitinib-sensitivity. In the highly gefitinib-sensitive NUGC-4, the biological response to NK4 (HGF antagonist/angiogenesis inhibitor) was examined. Subsequently, the composition of an NK4-expressing ternary complex (cationic lipid/nucleic acid/HMG-1, 2 protein) was optimized for maximum transfection activity in NUGC-4. Finally, mice were peritoneally coinoculated with NUGC-4 and scirrhous-associated gastric fibroblasts, NF22, on day 0. Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28). NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues. On day 28, both the hemoglobin concentration (g/dl) (control (n = 8), 11.9; treated (n = 8), 17.3; p = 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p = 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p = 0.0036) was significantly reduced. The median points of bloody ascite-free survival time (days) (control, 22; treated, 44; p < 0.0001) and time to euthanasia (days) (control, 36.5; treated, 56; p < 0.0001) were also significantly prolonged. This combination is a potentially useful approach to the treatment of peritoneal gefitinib-sensitive SGC dissemination.     

Efficacy of epidermal growth factor receptor-targeted molecular therapy in anaplastic thyroid cancer cell lines

Anaplastic thyroid cancer is one of the most aggressive human malignancies and the outcomes of conventional therapy have been far from satisfactory. Recently, epidermal growth factor receptor (EGFR)-targeted therapy has been introduced as an alternative therapeutic strategy for highly malignant cancers. This study was undertaken to investigate the expression of EGFR in anaplastic thyroid cancer cell lines, and to explore the potential of therapies targeting EGFR as a new therapeutic approach. EGFR was universally expressed in anaplastic cancer cell lines at a variety of levels. Specific EGFR stimulation with epidermal growth factor showed significant phosphorylation of ERK1/2 and Akt, and resulted in marked growth stimulation in an anaplastic thyroid cancer cell line, which highly expressed EGFR. This EGFR-transmitted proliferation effect of the cancer cell line was completely inhibited by gefitinib, an EGFR tyrosine kinase inhibitor. Moreover, growth of xenografts inoculated in mice was inhibited in a dose-dependent manner with 25-50 mg kg(-1) of gefitinib administrated orally. Inhibition of EGFR-transmitted growth stimulation by gefitinib was clearly observed in anaplastic thyroid cancer cell lines. Our results suggested that EGFR-targeted therapy, such as gefitinib, might be worth further investigation for the treatment of anaplastic thyroid cancer.     

非小细胞肺癌K-ras突变小分子对吉非替尼耐药细胞的作用

目的 观察针对K-ras突变小分子NSC-741909是否可特异性杀伤吉非替尼原发耐药细胞,并探讨其机制.方法 选取吉非替尼耐药细胞;观察NSC-741909作用后细胞增殖与凋亡的变化;共聚焦显微镜观察细胞骨架改变;Western blot检测K-ras、JNK、P-JNK的改变.结果 NSC-741909可使耐药细胞在作用24 h后,在1 μmol/L和2 μmol/L时,FITC-A+/PE-A+细胞增加至(6.9±0.6)%和(21.1±3.2)%(P＜0.01);作用30 min后,K-ras表达在2 h下降达70%;p-JNK表达增加,并持续至少15 h,而总JNK蛋白表达无改变;细胞骨架蛋白F-actin呈稀疏、不规则、发散状排列.结论 针对K-ras突变的小分子NSC-741909可特异性杀伤吉非替尼原发耐药细胞,这是通过持续激活JNK途径从而导致细胞凋亡实现的.

Abstract：

Objective To study whether a recently identified novel anticancer agent NSC-741909 can suppresses the growth of non-small cell lung cancer cell line ( NSCLC) which has primary resistance to Gefitinib and explore its molecular mechanisms. Methods Select NSCLC cell line which is resistant to Gefitinib. Observe the cell growth supression effect of NSC-741909 to the cell line, apoptosis and actin cytoskeleton changement. Observe K-ras, JNK, p-JNK protein expression by Western blotting. Results NSC-741909 can induce apoptosis of Gefitinib resistant cell lines at 24 h. At that time point, FITC-A +/ PE-A + increased to (6. 9 ±0.6)% and (21. 1 ±3.2)% (P ＜0. 01) at 1 and 2 μmol/L;K-ras protein decreased to 70% at 2 h; p-JNK expression was increased and lasted for at least 15 h and total JNK remained the same. Cell cytoskeleton F-actin presented as loose, irregular and radiation arrangement. Conclusion NSC-741909 which supress the mutant K-ras expression can induce the apoptosis of the NSCLC which is primary resistant to Gefitinib. This inhibition was mediated by sustained JNK activation.     

吉非替尼治疗16例晚期非小细胞肺癌的临床疗效

目的观察吉非替尼单药治疗晚期非小细胞肺癌（NSCLC）的疗效和不良反应。方法对16例化疗失败的晚期NSCLC患者给予吉非替尼口服250mg·d^-1,至病情进展或出现不可耐受的不良反应。结果 16例晚期NSCLC患者中,无完全缓解者,部分缓解（PR）4例（25.0%）,稳定（SD）6例（37.5%）,临床获益率（PR＋SD）为62.5%。临床获益率与性别、吸烟史及癌症分期无关。到随访截止日期,16例患者中,6例存活,10例死亡;中位肿瘤进展时间（TTP）为7个月,中位生存期（MST）为10个月。不良反应主要为Ⅰ～Ⅱ度皮疹和腹泻,对症处理后可缓解。结论吉非替尼有明显抗肿瘤作用,能明显提高晚期NSCLC患者的生活质量,改善临床症状,不良反应可以耐受。     

扶正消疹方联合吉非替尼治疗晚期非小细胞肺癌41例临床研究

目的观察扶正消疹方联合吉非替尼治疗晚期非小细胞肺癌（NSCLC）的临床疗效。方法41例非小细胞肺癌患者随机分为治疗组（21例）和对照组（20例）,对照组121服吉非替尼一日1次,每次250mg;治疗组存此基础上加用扶正消疹方一日1剂,分2次服。治疗2个月后评价近期疗效和不良反应。结果治疗组肿瘤治疗何效率为52．4％,控制率为81．0％;对照组分别为45．0％和75．0％,两组比较差异无统计学意义。治疗组皮疹发生率低于对照组,两组比较差异有统计学意义（P〈0．05）。结论联用扶正消疹方治疗晚期NSCLC可减少皮疹的发生率,且不影响吉非替尼疗效。     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Inhibitors of erbB-1 kinase

Epidermal growth factor receptor (EGFR or erbB-1) kinase inhibition continues to remain an important area of cancer research. The variety of small molecule agents undergoing clinical development can be divided into two groups: the reversible inhibitors of erbB-1 such as Iressa? (gefitinib, Astrazeneca) and Tarceva? (erlotinib, Pfizer) and the irreversible pan erbB inhibitors, such as CI-1033 and EKB-569. This application from Boehringer Ingelheim provides compounds that are described as inhibitors of erbB-1 kinase. Based on the structural similarity of these agents with EKB-569, these agents are likely to be irreversible pan erbB inhibitors.