【作者】 林琳；

【导师】 石远凯；

【作者基本信息】 北京协和医学院 ， 肿瘤内科学， 2014， 博士

【摘要】 目的：总结高剂量吉西他滨(GEM)与低剂量吉西他滨(GEM)联合顺铂(DDP)一线治疗晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)的近期疗效、毒性反应和总生存,评价吉西他滨(GEM)剂量在GP方案中的意义。方法：回顾性分析我院2003年3月至2009年3月107例接受GEM联合DDP治疗的初治晚期NSCLC患者。患者分别接受GEM<1100mg/m2(低剂量组)第1、8天,静滴或GEM≥1100mg/m2(高剂量组)第1、8天,静滴联合DDP75mg-80mg/m2,第1天,静滴或30mg/m2,连用3天,静滴,每三周为一周期治疗,每例患者完成2至4周期化疗。结果：低剂量组患者近期有效率(完全缓解+部分缓解)为30.9%,总的临床获益率(完全缓解+部分缓解+稳定)为81.8%。高剂量组患者近期有效率(完全缓解+部分缓解)为28.8%,总的临床获益率(完全缓解+部分缓解+稳定)为73.1%。中位随访3.33年(0.95年～7.08年),中位生存时间分别为652天和331天。主要的毒性反应为恶心呕吐等消化道反应和血液学毒性。其余的毒性反应较轻,可耐受。结论：吉西他滨联合顺铂一线治疗晚期非小细胞肺癌安全、有效,是标准方案之一。在国人中GEM<1100mg/m2更适合。背景与目的：表皮生长因子受体酪氨酸激酶抑制剂(Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, EGFR-TKIs)目前广泛应用于晚期非小细胞肺癌(non-small cell lung cancer, NSCLC),特别是存在表皮生长因子受体(Epidermal Growth Factor Receptor, EGFR)基因突变的肺腺癌患者。对于治疗后进展的患者,后续治疗未取得共识。本文总结EGFR-TKIs治疗获益后出现缓慢进展的晚期NSCLC患者接受不同后续治疗方法的近期疗效、毒性反应和总生存,评价不同治疗方法的意义。方法：回顾性分析我院2003年9月-2011年12月期间32例接受EGFR-TKIs治疗后缓慢进展的晚期NSCLC患者,分别继续接受EGFR-TKIs治疗或改行化疗。结果：EGFR-TKIs维持治疗组患者的中位生存时间为36.0月,在改行化疗的患者中,化疗有效率为43.25%,总的临床获益率(完全缓解+部分缓解+稳定)为86.5%。中位生存时间为15.5月。主要的毒性反应为恶心呕吐等消化道反应和血液学毒性。结论：在EGFR-TKIs治疗后出现肿瘤缓慢进展的患者中,维持原EGFR-TKIs治疗是可行的选择。目的：尽管在过去的半个世纪里研发出许多有效的抗肿瘤药物,但是如何使药物更好地作用于肿瘤细胞而减少对正常细胞的影响仍然是亟待解决的问题。纳米材料得益于其优越的运载能力和可能减少肿瘤细胞发生耐药的特性,近年来已用作药物运载体系。方法：本研究利用自组装立体结构DNA origami作为新型药物运载体系,克服了传统纳米材料由于生物相容性不足和立体结构表面工程缺陷导致的多功能活性障碍,将临床上广泛应用的化疗药物-阿霉素结合在DNA origami上。结果：DNA结构对于阿霉素有良好的装载率,而且负载药物的DNA结构不但对正常的乳腺癌细胞系产生了显著的抗肿瘤活性,更重要的是,对于阿霉素耐药的细胞系,通过增加耐药细胞对于阿霉素的摄取能够明显逆转其耐药表型。结论：DNA origami可以作为一种有效的、生物相容性好的药物载体和运载体系用药肿瘤治疗。更多还原

【Abstract】 Purpose: Through observing the effect、toxicity and overall survival of gemcitabine(GEM) combined with cisplantin(DDP) as first-line treatment of advanced non-small-cell lung cancer(NSCLC), we evaluate the importance of different gemcitabine dosage in the regimen.Methods: Retrospective review is conducted on107cases of chemotherapy-naive advanced NSCLC patients treated with GEM and DDP from March2003to March2009. Some patients received GEM<1100mg/m (low dosage group) while others received GEM≥1100mg/m2(high dosage group) on days1and8, and all received DDP75-80mg/m2on day1or30mg/m2for three days by intravenous administration, with21days as one cycle. Each patient received2-4cycles chemotherapy.Results: The total clinical response rate (complete and partial response) of low dosage group is30.9%, and clinical benefit rate (complete and partial response and stable disease) is81.8%. While the total clinical response rate (complete and partial response) of high dosage group is28.8%, and clinical benefit rate (complete and partial response and stable disease) is73.1%. After median follow-up of3.33years, the median overall survival periods are652days and331days respectively. The main toxicities are nausea, vomiting and hematological toxicities. Other toxicities are slight and tolerable.Conclusion: Combined chemotherapy with GEM plus DDP as first-line treatment to advanced NSCLC is an effective and feasible regimen, which is one of the standard regimens. And GEM<1100mg/m2is more suitable for Chinese. Background and Purpose: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used in the treatment of the advanced non-small cell lung cancer (NSCLC), especially in the adenocarcinoma patients with activating EGFR mutations. But there is no published overview of the following treatment. This report through observing the efficacy、toxicity and overall survival of different treatments to the advanced NSCLC patients who had gradual progression after EGFR-TKIs, evaluates the influence of the continued treatment and switching chemotherapy.Methods: Retrospective review is conducted on32cases of advanced NSCLC patients who experienced treatment failure of EGFR-TKIs. One group accepted the continued treatment and the other group accepted the switching chemotherapy.Results:The median overall survival of the continued treatment group is36.0months. The response rate of the switching chemotherapy group is43.25%, and clinical benefit rate (complete and partial response and stable disease) is86.5%. The median overall survival is15.5months. The main toxicities are nausea, vomiting and hematological toxicities.Conclusion:For the advanced NSCLC patients who had gradual progression after EGFR-TKIs, the continued treatment is one of the acceptable choices. Background and Purpose:Although a multitude of promising anti-cancer drugs have been developed over the past50years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance.Methods:However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to nanoparticles widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation.Results: A high level of drug loading efficiency was achieved and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells, but more importantly to Doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance.Conclusion:DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.更多还原