姜黄素与5 氟尿嘧啶对人白血病K562细胞体外抗癌的协同作用

用ＭＴＴ 法及ＡＯ／ＥＢ 荧光法观察了姜黄素与５氟尿嘧啶对人白血病Ｋ５６２ 细胞体外抗癌的协同作用，结果发现姜黄素与５氟尿嘧啶合用有相加甚至增强作用，尤其是对诱导细胞凋亡的协同作用更为突出。

家兔氟尿嘧啶胃左动脉灌注与静脉化疗药物动力学比较

目的 评价氟尿嘧啶动物胃左动脉灌注和外周静脉化疗药物动力学的基础实验比较。方法 实验家兔 18只 ,随机分 6个时间组 ,由胃左动脉注入氟尿嘧啶 (按 5 0mg/kg) ,于不同时间点 ,留取门静脉及外周静脉血 ,同时处死动物 ,取部分胃组织。血样及组织样经处理后采用高效液相色谱测定 ,对照组由耳缘静脉注入氟尿嘧啶 (5 0mg/kg) ,不同时间取血和组织 ,同上处理后测定。 结果 两种途径给药后的门静脉及外周静脉的药时曲线均为 5min达到高峰值 ,之后迅速下降 ,30min后下降缓慢 ,符合二室模型 ;动脉灌注组门静脉血药浓度明显高于外周血药浓度 ,亦明显高于静脉注药组的门静脉浓度 ,而且持续时间较长 ;5min后动脉灌注组胃组织药物浓度 11倍于静脉给药组 ,2h后两者浓度接近。结论 经胃左动脉灌注在门静脉及胃组织中的药物浓度在较长时间内维持相对高的水平 ,而且能使局部药物相对集中 。

经造口灌注氟尿嘧啶治疗未切除的大肠癌

由上海第二医学院瑞金医院采用经肛门给予氟尿嘧啶（５Ｆｕ）作为不能切除的晚期直肠癌术前辅助化疗，大大提高了癌灶和引流淋巴结中的药物浓度，降低了骨髓、肺和肝脏中的浓度，有利于提高疗效，减少毒副作用［１］。但是药物难以保留较长时间。自１９９５年５月～１９...

植入用缓释氟尿嘧啶的人体内血药浓度经时方程初探

目的 :探讨并建立植入用缓释氟尿嘧啶的人体内血浆浓度经时模型。方法 :分析体内过程 ,建立微分方程 ,求解与证明。结果 :经 19例试验者数据拟合 ,其人体内血药浓度经时模型为 :单室开放式模型 ,血药浓度方程C =A1 e-Ket+A2 e-Kat+A3e-Krt。结论 :此方程为植入剂药代动力学参数的计算提供理论参数。

马外生殖器鳞状细胞癌5－氟尿嘧淀局部治疗

对１０匹经组织学检查证实为鳞状细胞癌（ＳＣＣ）和１匹疑为外生殖器ＳＣＣ的患马采用清创结合局部应用５－氟尿嘧啶（５－Ｆｕ）或只局部用药治疗，所有患马的肿瘤均已消退，且无复发。５－Ｆｕ的局部应用。

曲氟尿苷替匹嘧啶在消化道肿瘤中的研究进展

曲氟尿苷替匹嘧啶(TAS-102)是一种由曲氟尿苷(FTD)和胸苷磷酸化酶抑制剂(TPI)组成的口服化疗药物。体外和异种移植模型均证实TAS-102对5-氟尿嘧啶耐药的肿瘤具有抗肿瘤活性。基于Ⅲ期临床试验中TAS-102为患者带来生存获益,目前已被批准用于转移性结直肠癌和胃癌患者的三线治疗。近年来,有研究初步表明TAS-102在各种消化道肿瘤中均有一定疗效。本文总结了TAS-102在消化道肿瘤中的临床应用,并对TAS-102联合其他抗肿瘤药物的合理性及临床获益进行综述。

曲氟尿苷替匹嘧啶联合贝伐珠单抗治疗难治性转移性结直肠癌的疗效与安全性的meta分析

目的系统分析曲氟尿苷替匹嘧啶(trifluridine-tipiracil/TAS-102,T)联合贝伐珠单抗(bevacizumab,B)相较于TAS-102单药在既往标准治疗失败或不耐受的难治性转移性结直肠癌(metastastic colorectal cancer,m CRC)应用中的有效性和安全性。方法在PubMed、Embase和Cochrane Library中进行文献检索,检索时限为自建库至2020年7月,并对纳入的文献进行meta分析,并采用相对危险度(relative risk,RR)及风险比(hazard ratio,HR)作为合并效应量。结果共纳入4篇文献,包括1项随机对照试验(randomized controlled trial,RCT)和3项回顾性研究,共338例患者(T+B组:163例,T组:175例)。T+B组疾病控制率(RR=1.71,95%CI:1.11~2.61,P=0.01)、无进展生存期(HR=0.59,95%CI:0.44~0.78,P=0.0002)、总生存期(HR=0.58,95%CI:0.43~0.79,P=0.0006)均高于T组。在任何级别的不良事件中,T+B组中性粒细胞减少症、血小板减少症、高血压、蛋白尿的发生率均高于T组(P<0.05);而两组之间的贫血、恶心、腹泻、呕吐、粒细胞减少性发热、疲乏等症状的差异均无统计学意义(P>0.05);T+B组中3级以上的中性粒细胞减少症与贫血的发生率高于T组(P<0.05)。结论对于难治性m CRC患者,TAS-102联合贝伐珠单抗治疗后的疾病控制率、无进展生存期及总生存期均优于TAS-102单药治疗,但中性粒细胞减少症、血小板减少症、贫血(逸3级)、高血压、蛋白尿发生率较高。

乌体林斯联合草酸铂加氟苷方案治疗进展期胃癌的临床观察

目的 :观察乌体林斯联合草酸铂加氟苷方案治疗进展期胃癌的疗效和不良反应。方法 :30例进展期胃癌按以下方案治疗 :草酸铂 130mg/m2 ivdrop 2hdl,CF15 0mg/m2 ivdropdl～ 5 ,5 -FU5 0 0mg/m2 ivdropdl～ 5 ;乌体林斯 1.72 μg(1ml)im5 /qw。每 3周重复 ,3周期后评价疗效。 结果 :CR3例 ,PR15例 ,NC8例 ,PD4例 ,总有效率 6 0 %,毒副反应主要为I -II级消化道和骨髓毒副作用。结论 :乌体林斯联合草酸铂加氟苷方案治疗进展期胃癌疗效好 ,耐受性好。

卵巢癌腹腔化疗的药代动力学特征

目的 :探讨卵巢癌腹腔化疗药物的药代动力学特征。方法 :10例原发性卵巢上皮性癌患者 ,手术后 1周行以DDP +5 FU为主的腹腔化疗 ,剂量为DDP 6 0mg m2 ,5 FU 75 0mg m2 。于腹腔注射完毕后 0 .5、1、2、6、2 4小时分别取血样 ,用HPLC及原子吸收光谱法分别测定血清 5 FU和总铂浓度。数据以药代动力学软件 3P87处理。结果 :腹腔注射后 ,5 FU、DDP血清平均浓度的变化过程符合一级吸收的单室药代动力学模型。其参数分别为 :5 FU :Ke =0 .4 5± 0 .18 h、Ka =7.5 9± 4 .6 3 h、T(peak) =0 .87± 0 .30h、C(max) =2 .4 6± 1.12 μg ml、AUC =8.38± 4 .71μg·h ml、Vd =316± 6 9.4ml kg ;DDP :Ke =0 .0 14± 0 .0 1 h、Ka =1.31± 1.0 3 h、T(peak) =4 .72± 2 .81h、C(max)=0 .85± 0 .2 8μg ml、AUC =85 .6± 5 5 .7μg·h ml、Vd =6 0 .3± 32 .6ml kg。 5 FU ,AUC0～ 2 4h =8.4 μg·h ml;DDP ,AUC0～ 2 4h=14 .4 μg·h ml。结论 :从药代动力学方面看 ,腹腔化疗中 5 FU的AUC不低于相同剂量静脉给药 。

不同新辅助化疗方案治疗乳腺癌的临床观察

目的比较2组不同新辅助化疗方案的疗效及毒性反应。方法80例Ⅱ、Ⅲ期乳腺癌随机分为2组,每组40例。A组用CTF方案（环磷酰胺＋吡柔比星＋5-氟尿嘧碇）,B组用TT方案（吡柔比星＋紫杉醇）新辅助化疗。3～4周为1个周期,所有患者在完成2个周期新辅助化疗后评价疗效。结果CTF组总有效率为52.5%,TT组的总有效率为82.5%,差异有统计学意义（P〈0.05）。2组白细胞下降率,胃肠道反应相似;TT组脱发程度较重,伴有关节肌肉疼痛,神经毒性及面色潮红等毒性反应,但程度较轻,可以耐受。结论2组新辅助化疗方案对乳腺癌治疗均有效,毒性反应均可耐受。TT组疗效及毒性反应均高于CTF组。

聚乳酸共聚物复合缓释药物的材料特征与实验应用

背景:聚乳酸共聚物复合药物缓释材料能够降低药物的毒副作用,延长药物作用时间,提高药物治疗效果,是目前药物研究的热点之一。目的:明确各种聚乳酸共聚物复合药物缓释材料的特征以及实验应用效果。方法:将不同种类的药物与聚乳酸进行共聚结合形成聚乳酸共聚物复合药物缓释材料,分析多种聚乳酸共聚物复合药物缓释材料的释药特征,并分析动物实验研究中聚乳酸共聚物复合缓释药物材料的治疗效果。结果与结论:研究发现多种治疗药物均可以与聚乳酸结合形成聚乳酸共聚物复合药物缓释材料系统,其中包括抗肿瘤类药物、抗菌、抗病毒类药物、抗结核类药物、心脑血管疾病防治类药物以及代谢类药物。这些药物与聚乳酸结合形成共聚物缓释系统后,可以延长药物作用时间,有效稳定血药浓度,达到靶向性治疗的作用,明显提高药物治疗作用效果。

瑞戈非尼、呋喹替尼、TAS-102治疗转移性结直肠癌的疗效及安全性的Meta分析

目的 系统评价瑞戈非尼、呋喹替尼、曲氟尿苷替匹嘧啶(TAS-102)治疗转移性结直肠癌(mCRC)的疗效及安全性,以有效指导临床医师进行合理用药。方法 利用计算机检索Cochrane Library、PubMed、Google school、Embase、中国知网等数据库,检索时限为建库至2022年12月30日。收集瑞戈非尼、呋喹替尼、TAS-102治疗mCRC疗效及安全性的随机对照试验,采用Cochrane 6.1评分系统对文献进行系统评估,提取总生存期(OS)、无进展生存期(PFS)、客观缓解率(ORR)、疾病控制率(DCR)及药品不良反应(ADR)信息,采用RevMan 5.3、ITC软件进行分析。结果 纳入文献6篇,其中瑞戈非尼相关文献2篇,包括瑞戈非尼组641例,对照组323例;呋喹替尼相关文献2篇,包括呋喹替尼组325例,对照组162例;TAS-102相关文献2篇,包括TAS-102组805例,对照组401例。Meta分析结果显示,瑞戈非尼组、呋喹替尼组、TAS-102组的OS、PFS长于对照组,DCR高于对照组(P<0.01);瑞戈非尼组、呋喹替尼组、TAS-102组的ORR与对照组比较差异无统计学意义(P>0.05);瑞戈非尼组、呋喹替尼组3级以上ADR发生率高于对照组(P<0.05),TAS-102组3级以上ADR发生率与对照组比较差异无统计学意义(P>0.05)。瑞戈非尼组、呋喹替尼组、TAS-102组的OS、ORR、DCR及3级以上ADR发生率比较差异均无统计学意义(P>0.05),但呋喹替尼组的PFS长于TAS-102组(P<0.05)。结论 瑞戈非尼、呋喹替尼、TAS-102作为治疗mCRC的新型化疗药物,其临床抗癌活性均较为可观,且均存在ADR,但呋喹替尼的PFS更优。

曲氟尿苷替匹嘧啶在晚期大肠癌后线治疗中的探索

目的分析曲氟尿苷替匹喘睫在晚期大肠癌后线治疗效果。方法回顾性收集在2020年6月-2021年6月我院晚期大肠癌13名患者的资料,这些患者均接受白蛋白紫杉醇+曲氟尿昔替匹喀喘+免疫检查点抑制剂+抗血管药物的治疗方案,主要的疗效观察指标包括客观缓解率、无进展生存期和总生存。结果13名患者中仅有2名患者出现客观缓解(ORR=15.4%,95%CI:1.9%-45.4%),10名患者在接受治疗后得到疾病控制(DCR=76.9%,95%CI:46.2%-95.0%)。整体人群中位随访时间337d(范围:166-8664),中位PFS为134<1(95%CI:105.8-162.2d);ECOG=1分的患者接受该治疗方案的无进展生存期明显长于ECOG=2分的患者(ECOG=1分:179d vs ECOG=2分:126d,p=0.04,HR=0.38,95%CI:0.12 to 1.2).最常见的不良事件为骨髓抑制、手脚麻木、手足综合征、恶心、食欲减退、乏力和血压升高,其中绝大多数为1-2级。有4名患者出现≥3级白细胞/中性粒细胞减少。结论白蛋白紫杉醇+曲氟尿昔替匹喀睫+免疫检查点抑制剂+抗血管药物的联合方案后线治疗微卫星稳定的大肠癌其总体效果仍然有限(对照既往多项的历史数据,疗效提升并不明显),但本研究结果提示未来在扩大样本量的基础之上,可针对体能状况较好的患者探索强强联合的治疗方案。

Prevention of metastasis to liver by using 5-FU intraperitoneal chemotherapy in nude mice inoculated with human colonic cancer cells

AIMS Using a new approach of regional adjuvant chemotherapy to prevent cancer cells hepatic metasta- sis after radical surgery of large bowel cancer. METHODS A model of liver with metastasis of hu- man colonic cancer (HCC) cells in nude mice was used to observe the effect in prevention of metastasis of HCC cells inoculated via spleen applied with early postoper- ative intraperitoneal (IP) chemotherapy using large dose of 5-FU. RESULTS The incidence of metastasis to liver was decreased by 40%,the mean number of metastatic liv- er nodules in each animal was reduced by 50.89% and the mean survival times of each animal was prolonged by 48.21% by using 5-FU 40 mg/NS 40 ml/kg IP for two consecutive days as compared with the controls. CONCLUSIONS IP is a new and more effective re- gional adjuvant chemotheraputic approach in the pre- vention of liver metastasis HCC cells after radical surgery of large bowel cancer.

Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

Objective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy onhepatocarcinoma-bearing rats, and examine the action between calcium channel blockers and cytotoxic drugs.Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of livercarcinoma-bearing rats. All experimental animals were divided into four groups. On the sixth day post implantation, in group A (controlgroup) 6 ml of saline was injected intraperitoneally once a day for 3 days. In group B (single chemotherapy group) 6 ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days. In group C (combination of treatment group) both 5-Fu (75 mg/kg) and verapamil(25 mg/kg) were administered simultaneously as in A and B. In group D (simple verapamil group) only 6 ml of verapamil (25 mg/kg)was administered as above.Results Compared with groups A, B and D, The volume of cancer and the contents of liver cancer DNA and protein were significantlyreduced. The rates of inhibiting cancer (89.9% in group C and 35.4% in group B) were significantly increased in group C. Group C hadsignificantly long survival time compared to groups A, B and D ( P < 0.05) . By light microscopy, a number of focal necroses were foundin cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitoneal chemotherapy to liver cancer ; Theuse of verapamil can not increase the toxicity of 5-Fu.

大肠癌术后早期5-Fu腹腔化疗的临床研究

目的探讨大肠癌术后早期大剂量大容积5-Fu 腹腔化疗(IPC)的可行性和疗效。方法全组62例结、直肠癌患者,共接受 54疗程770次 IPC。化疗期间观察毒性反应、对肝功影响及并发症等。随访6～42个月,平均16个月。结果全组无严重毒副作用和并发症。随访结果与同期其它化疗方法差异有显著性(P<0.05)。结论 IPC 简便易行、安全,是结、直肠癌术后早期有前途的辅助化疗措施。

The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines

AIM:There are conflicting data about p53 function on cellular sensitivity to the cytotoxic action of 5-fluorouracil (5-FU). Therefore the objective of this study was to determine the combined effects of adenovirus-mediated wild-type (wt) p53 gene transfer and 5-FU chemotherapy on pancreatic cancer cells with different p53 gene status. METHODS:Human pancreatic cancer cell lines Capan-1^(p53mut), Capan-2^(p53wt),FAMPAC^(p53mut),PANC1^(p53mut),and rat pancreatic cancer cell lines AS^(p53wt) and DSL6A^(p53null) were used for in vitro studies.Following infection with different ratios of Ad- p53-particles (MOI) in combination with 5-FU,proliferation of tumor cells and apoptosis were quantified by cell proliferation assay (WST-1) and FACS (PI-staining).In addition,DSL6A syngeneic pancreatic tumor cells were inoculated subcutaneously in to Lewis rats for in vivo studies. Tumor size,apoptosis (TUNEL) and survival were determined. RESULTS:Ad-p53 gene transfer combined with 5-FU significantly inhibited tumor cell proliferation and substantially enhanced apoptosis in all four cell lines with an alteration in the p53 gene compared to those two cell lines containing wt-p53.In vivo experiments showed the most effective tumor regression in animals treated with Ad-p53 plus 5-FU.Both in vitro and in vivo analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by 5-FU. CONCLUSION:Our results suggest that Ad-p53 may synergistically enhance 5-FU-chemosensitivity most strikingly in pancreatic cancer cells lacking p53 function.These findings illustrate that the anticancer efficacy of this combination treatment is dependent on the p53 gene status of the target tumor cells.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Preparation of chitosan-polyaspartic acid-5-fluorouracil nanoparticles and its anti-carcinoma effect on tumor growth in nude mice

AIM: To prepare chitosan-polyaspartic acid-5-fluorouracil (CTS-Pasp-5Fu) nanoparticles and investigate its anti-carcinoma effect and toxicity. METHODS: CTS-Pasp-5Fu nanoparticles were synthesized by ionic gelatification. Male BABL/c nude mice were injected with SGC-7901 gastric carcinoma cell line mass to establish a human gastric carcinoma model. They were randomly allocated into 4 groups: CTS-Pasp-5Fu (containing 5-Fu 1.25 mg/kg), 5-Fu (1.25 mg/kg), CTS-Pasp and normal saline groups. Tumor weight was measured and assay of colony forming unit-granulocyte and macrophage (CFU-GM) was performed. The structural change of cells and tissues was observed and the Bax and Bcl-2 genes were detected. RESULTS: Compared with normal saline, the inhibition rates of tumor growth for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.58%, 58.69% and 70.82%, respectively. The tumor inhibition rates for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.09%, 65.3% and 72.79%, respectively. There was a significant decrease in the number of CFU-GMformation and increase of total bilirubin, and alanine aminotransferase in the 5-Fu group, but no change in those of the other three groups. There was no change in white blood cell count and creatinine among the four groups. Pathological section of liver and nephridial tissues showed that the damage in the 5-Fu group was more severe than that in the CTS-Pasp-5Fu group. 5-Fu and CTS-Pasp-5Fu groups could both down-regulate the Bcl-2 expression and up-regulate the Bax expression to different extent, and the accommodate effect of CTS-Pasp-5Fu was more obvious than 5-Fu. CONCLUSION: The tumor inhibition rate of CTS-Pasp-5Fu nanoparticles is much higher than that of 5-Fu alone.