培美曲塞与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效与安全性

目的：探讨培美曲塞联合顺铂与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效和安全性。方法回顾性分析64例恶性胸膜间皮瘤患者的临床资料,采用培美曲塞联合顺铂化疗的纳入PP组（32例）,采用雷替曲塞联合顺铂方案的为RP 组（32例）,比较两组不同化疗方案的疗效及不良反应。结果两组患者客观有效率、疾病控制率比较,差异均无统计学意义（χ2分别=2.35、3.76,P均＞0.05）。PP组患者中位总生存期为11.62个月,中位无疾病进展生存期为5.61个月;RP组患者中位总生存期为11.33个月,中位无疾病进展生存期为4.93个月,两组患者在中位总生存期、中位无疾病进展生存期之间的差异均无统计学意义（t分别=1.06、2.08,P均＞0.05）。两组患者不良反应均以骨髓抑制和胃肠道反应为主,两组之间不良反应比较,差异无统计学意义（χ2=2.82,P＞0.05）。结论培美曲塞或雷替曲塞联合顺铂用于MPM的临床疗效相当,对于经济条件较差的MPM患者来说,选用雷替曲塞联合顺铂治疗也可以作为MPM的一线方案。     

贝伐珠单抗联合伊立替康与雷替曲塞治疗氟尿嘧啶耐药晚期结直肠癌的疗效和安全性

目的 观察贝伐珠单抗联合伊立替康与雷替曲塞方案在氟尿嘧啶类药物耐药后的晚期结直肠癌患者中的疗效及安全性。方法 收集中国医科大学附属第一医院2014—2019年收治的氟尿嘧啶类耐药的60例晚期结直肠癌患者,对照组30例,应用伊立替康联合雷替曲塞方案（IR）;实验组30例,应用IR联合贝伐珠单抗方案。分析比较两组患者的客观有效率（ORR）、疾病控制率（DCR）、无进展生存时间（PFS）及不良反应发生情况。结果 实验组和对照组ORR分别为6.67%和3.33%,DCR分别为66.67%和53.33%,两组ORR和DCR比较差异无统计学意义。实验组和对照组中位PFS分别为6.0个月和3.1个月,差异有统计学意义（P=0.020 4）。两组不良反应以Ⅰ/Ⅱ级多见,Ⅲ/Ⅳ级不良反应发生率低,实验组蛋白尿的发生率高于对照组,差异有统计学意义（P=0.001）。其余如出血、转氨酶升高、恶心、呕吐、腹泻、发热、皮疹、高血压等不良反应发生率均为实验组高于对照组,但差异无统计学意义。结论 贝伐珠单抗联合伊立替康与雷替曲塞方案可提高既往氟尿嘧啶类治疗耐药后的晚期结直肠癌患者的疗效,无进展生存期增加,不良反应可耐受,值得进一步研究。     

Antimetabolites and cancer: emerging data with a focus on antifolates

Antimetabolites, especially antifolates, play an important role in the treatment of a variety of both malignant, and non-malignant diseases, such as rheumatoid arthritis, and bacterial and parasitic infections. Recently, new antimetabolites have become an area for anticancer drug expansion. Gemcitabine has emerged as an important new agent in several tumour types, including non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also been developed; raltitrexed and pemetrexed are now commercially available for the treatment of mesothelioma, non-small cell lung cancer and other solid cancer types. This review will describe the most recent findings and their potential clinical applications.     

雷替曲塞加奥沙利铂对比PF方案放化疗治疗食管癌的临床观察

目的:观察雷替曲塞+ 奥沙利铂化疗对比5- 氟尿嘧啶（5-FU ）联合顺铂的方案（PF方案）同步放化疗治疗中晚期食管癌的近期疗效及不良反应。方法:选取2012年1 月至2014年12月连云港节第二人民医院84例病理确诊的中晚期食管癌患者,随机分为试验组雷替曲塞+ 奥沙利铂方案同步放化疗40例和对照组PF方案同步放化疗44例,采用三维适形放疗（DT= 60Gy/30f）。 化疗方案:试验组为雷替曲塞2.5 mg/m2,静滴d1,奥沙利铂130 mg/m2,静滴d2;对照组为5-FU 500 mg/m2,静滴d1～5,顺铂25mg/m2,静滴d1～3。化疗均于放疗第1、29d 应用,化疗2 个周期。比较两组患者的近期疗效和不良反应。结果:试验组缓解率（response rate ,RR）、完全缓解（completeresponse,CR）、1 年生存率均高于对照组（87.50% vs . 79.54% ,P = 0.329;32.50% vs . 18.18% ,P = 0.130;82.50% vs . 79.50% ,P=0.701）,差异均无统计学意义。不良反应方面,试验组恶心呕吐、食欲不振、白细胞下降、放射性食管炎、心脏毒性明显减轻（P < 0.05）,其他不良反应两组相似（P> 0.05）。 结论:雷替曲塞+ 奥沙利铂方案联合放化疗治疗中晚期食管癌患者,近期疗效与PF方案同步放化疗相当,治疗不良反应明显下降,值得临床进一步行多中心、大样本研究。      

雷替曲塞用于腹膜假黏液瘤肿瘤细胞减灭术后腹腔热灌注化疗的短期疗效及安全性分析

目的:观察雷替曲塞用于腹膜假黏液瘤(pseudomyxoma peritonei,PMP）肿瘤细胞减灭术(cytoreductive surgery,CRS)后腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC）的短期疗效及安全性。方法:回顾性分析我院自2019年01月至2020年03月接受CRS联合HIPEC治疗的PMP患者,根据术后灌注药物方案是否应用雷替曲塞分为观察组和对照组。观察组术后第1次灌注药物为雷替曲塞(4 mg),第2~5次灌注药物为5-氟尿嘧啶（5-FU）(1 g);对照组术后5次灌注药物均采用5-FU(1 g)。比较两组患者术后一般情况、手术并发症发生率、排气时间、住院时间及两组患者手术前后血常规(WBC、PLT)、肝功能(ALT、AST)、肾功能(Cr)变化情况。结果:研究期间接受CRS及HIPEC治疗的患者共86例,其中观察组和对照组分别为39例和47例。两组基线资料一致(P＞0.05)。两组间术后出血、肠瘘、胸腔积液、切口感染等并发症发生率比较无统计学差异（P＞0.05）。化疗相关不良反应显示对照组腹痛发生率较观察组多(P=0.044),其余不良反应如恶心、呕吐、乏力、发热3日以上等两组比较均无统计学差异（P＞0.05）。两组患者手术前后血液学检查结果变化无统计学差异（P＞0.05）。结论:雷替曲塞用于PMP CRS后HIPEC,不增加术后并发症,不良反应可耐受,治疗过程安全性良好。     

伊立替康联合雷替曲塞3周方案二线治疗晚期结直肠癌的疗效观察

目的:观察伊立替康联合雷替曲塞二线治疗晚期结直肠癌的疗效及安全性.方法 :对22例一线治疗失败的晚期结直肠癌病人予以二线治疗:伊立替康180 mg/m2,静脉滴注1 h,第1天;雷替曲塞3 mg/m2,静脉滴注15 min,第2天;21 d为1个周期.每2个周期评价疗效,并分析其安全性.结果 :22例病人均可评价近期疗效,其中完全缓解1例,部分缓解4例,疾病稳定11例,疾病进展6例,客观有效率为22.7%,疾病控制率为72.7%,病人的中位肿瘤进展时间为5.0个月,中位总生存时间11.8个月.严重不良反应为中性粒细胞减少和腹泻,发生率分别为13.6%和4.5%.结论 :伊立替康联合雷替曲塞在晚期结直肠癌的二线化疗中,有效率较高,不良反应能够耐受,值得在临床上推广.     

雷替曲塞对人胃癌细胞MGC-803裸鼠移植瘤的抑制作用

 目的 通过研究雷替曲塞抑制裸鼠MGC-803胃癌移植瘤的生长,初步探讨其相关作用机制。方法 建立人胃癌裸鼠皮下移植瘤模型,把24只裸鼠随机分为3 组,每组8只。对照组(生理盐水),低剂量组(雷替曲塞5 mg/kg),高剂量组(雷替曲塞12 mg/kg)。每周经腹腔注射给药2次,持续2周。详细记录裸鼠精神状态、体重以及肿瘤生长情况,免疫组化法检测裸鼠肿瘤组织Ki67及PCNA蛋白表达,并通过Western blottting法检测裸鼠肿瘤组织Caspase-3及Bax蛋白表达。结果 治疗期间雷替曲塞低剂量组和高剂量组裸鼠体重均低于对照组,低剂量组、高剂量组的抑瘤率分别为27.54%、44.20%,差异有统计学意义(P<0.05);免疫组化法显示低剂量组、高剂量组Ki67阳性细胞率分别为58.95%、42.16%,PCNA阳性细胞率分别为51.36%、37.27%,均明显低于对照组(P<0.05);Western blotting法表明低剂量组、高剂量组Caspase-3和Bax蛋白表达均明显高于对照组(P<0.05)。结论 雷替曲塞可抑制人胃癌裸鼠移植瘤的生长增殖,其机制可能与提高Caspase-3和Bax蛋白表达、从而促进细胞凋亡有关。     

Uracil in DNA: consequences for carcinogenesis and chemotherapy

The synthesis of thymidylate (TMP) occupies a convergence of two critical metabolic pathways: folate metabolism and pyrimidine biosynthesis. Thymidylate is formed from deoxyuridylate (dUMP) using N(5),N(10)-methylene tetrahydrofolate. The metabolic relationship between dUMP, TMP, and folate has been the subject of cancer research from prevention to chemotherapy. Thymidylate stress is induced by nutritional deficiency of folic acid, defects in folate metabolism, and by antifolate and fluoropyrimidine chemotherapeutics. Both classes of chemotherapeutics remain mainstay treatments against solid tumors. Because of the close relationship between dUMP and TMP, thymidylate stress is associated with increased incorporation of uracil into DNA. Genomic uracil is removed by uracil DNA glycosylases of base excision repair (BER). Unfortunately, BER is apparently problematic during thymidylate stress. Because BER requires a DNA resynthesis step, elevated dUTP causes reintroduction of genomic uracil. BER strand break intermediates are clastogenic if not repaired. Thus, BER during thymidylate stress appears to cause genome instability, yet might also contribute to the mechanism of action for antifolates and fluoropyrimidines. However, the precise roles of BER and its components during thymidylate stress remain unclear. In particular, links between BER and downstream events remain poorly defined, including damage signaling pathways and homologous recombination (HR). Evidence is growing that HR responds to persistent BER strand break intermediates and DNA damage signaling pathways mediate cross talk between BER and HR. Examination of crosstalk among BER, HR, and damage signaling may shed light on decades of investigation and provide insight for development of novel chemopreventive and chemotherapeutic approaches.     

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.     

抗癌药雷替曲塞的合成

目的研究抗癌药雷替曲塞的合成。方法以2-噻吩甲醛为起始原料,经硝化、氧化、酯化、还原、氨基保护、N-甲基化、水解、缩合、脱保护、N-烷基化、水解11步反应合成雷替曲塞。结果与结论总收率为12.9%,其结构经核磁共振氢谱、质谱确证。