Determination of Residues and Safety Analysis of Metal Impurities in Platinum-based Antitumor Drugs

The residual metal impurities in cisplatin, carboplatin and oxaliplatin were determined by ICP-AES. The samples were ignited and dissolved with HCl:HNO 3 (3:1). The method is simple and accurate. By the determination of the metal residues in the samples, the calculated actual daily exposure and concentration of the metal Pd, Ir, Rh, Ru, Mo, Ni, Cr, V, Cu, Mn, Fe and Zn that were less than the permitted daily exposures (PDE) and the limited concentration permitted in the EMEA guideline on the specification limits for residues of metal catalysts or metal reagents [1] . The metal residues can de adequately removed from the active pharmaceutical ingredients and the corresponding drugs. The trace metal residues will not affect human health and lead to the safety hazard by the intravenous injection.

EFFECT OF ANTITUMOR DRUGS ON THE ACTIVITY OF DNA TOPOISOMERASE I

The activity of DNA topoisomerase Ⅱ prepared from either normal or tumor tissues were compared. It was found that the unknotting activity of the enzyme in malignant tumor cells was higher than that in normal cells. We selected some antitumor drugs including Chinese traditional medicine, and observed their effects on the unknotting activity of topoisomerase Ⅱ. The results showed that inhibition of the unknotting activity of the enzyme required very low concentrations of drugs, but much higher concentrations were required for other tested. Some antitumor drugs had no effect on the enzyme were also proved. It is interesting that carrageenan, an antiviral drug, strongly blocked the unknotting activity although its antitumor activity has not been reported.

Antitumor drug-induced acute pancreatitis:report of a special case

Drug-induced acute pancreatitis （DAP） is defined as pancreatitis with corresponding clinical manifestations resulted from drug-induced pancreatic secretion dysfunction and pancreatic tissue damage. One case of DAP resulted from chemotherapeutics （Nimustine） was diagnosed and treated our in hospital in 2009. This patient belonged to pancreatitis induced by anticancer drugs, and the toxicity of anticancer drugs acted directly on pancreatic cells, leading to the occurrence of pancreatitis. After treatment, the pancreatitis was effectively treated in this patient, but the final the patient and his family eventually gave up the treatment due to aggravated primary diseases

Recent advances regarding the role of ABC subfamily C member 10(ABCC10) in the efflux of antitumor drugs

ABCC10,also known as multidrug-resistant protein 7(MRP7),is the tenth member of the C subfamily of the ATP-binding cassette(ABC) superfamily.ABCC10 mediates multidrug resistance(MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs.The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane.ABCC10 is a broad-specificity transporter of xenobiotics,including antitumor drugs,such as taxanes,epothilone B,vinca alkaloids,and cytarabine,as well as modulators of the estrogen pathway,such as tamoxifen.In recent years,ABCC10 inhibitors,including cepharanthine,lapatinib,erlotinib,nilotinib,imatinib,sildenafil,and vardenafil,have been reported to overcome ABCC10-mediated MDR.This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy,particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.

Homology modeling and structural analysis of human <i>γ</i>-glutamylcysteine ligase catalytic subunit for antitumor drug development

Homology modeling and structural analysis of human glutamate cysteine ligase catalytic subunit (hGCLC) were performed with a software package the Molecular Operating Environment. A yeast GCLC (yGCLC;PDB code: 3LVV) was selected as a template for the 3D structure modeling of hGCLC. The modeled hGCLC showed significant 3D similarities at the ligand biding site (LBS) to the yGCLC structure. The contact energy profiles of the hGCLC model were in good agreement with those of the yGCLC structure. Ramachandran plots revealed that only 1.4% of the amino acid residues were in the disfavored region for hGCLC. The molecular electrostatic potential (MEP) map of the hGCLC model exhibited that the model was slightly different from the yGCLC model electrostatically at the LBS. Further, docking simulations revealed the similarity of the ligand-receptor bound location between the hGCLC and yGCLC models. The different binding orientations between the glutathione (GSH)-hGCLC and GSH-yGCLC complexes reflected the different MEP maps at the LBSs between the hGCLC and yGCLC models. These results indicate that the hGCLC model was successfully modeled and analyzed. To the best of our knowledge, this is the first report of a hGCLC model with detailed analyses, and our data verify that the model can be utilized for application to target hGCLC for the development of anticancer drugs.

3D bioprinting of in vitro porous hepatoma models:establishment,evaluation,and anticancer drug testing

Traditional tumor models do not tend to accurately simulate tumor growth in vitro or enable personalized treatment and are particularly unable to discover more beneficial targeted drugs.To address this,this study describes the use of threedimensional(3D)bioprinting technology to construct a 3D model with human hepatocarcinoma SMMC-7721 cells(3DP-7721)by combining gelatin methacrylate(GelMA)and poly(ethylene oxide)(PEO)as two immiscible aqueous phases to form a bioink and innovatively applying fluorescent carbon quantum dots for long-term tracking of cells.The GelMA(10%,mass fraction)and PEO(1.6%,mass fraction)hydrogel with 3:1 volume ratio offered distinct pore-forming characteristics,satisfactorymechanical properties,and biocompatibility for the creation of the 3DP-7721 model.Immunofluorescence analysis and quantitative real-time fluorescence polymerase chain reaction(PCR)were used to evaluate the biological properties of the model.Compared with the two-dimensional culture cell model(2D-7721)and the 3D mixed culture cell model(3DM-7721),3DP-7721 significantly improved the proliferation of cells and expression of tumor-related proteins and genes.Moreover,we evaluated the differences between the three culture models and the effectiveness of antitumor drugs in the three models and discovered that the efficacy of antitumor drugs varied because of significant differences in resistance proteins and genes between the three models.In addition,the comparison of tumor formation in the three models found that the cells cultured by the 3DP-7721 model had strong tumorigenicity in nude mice.Immunohistochemical evaluation of the levels of biochemical indicators related to the formation of solid tumors showed that the 3DP-7721 model group exhibited pathological characteristics of malignant tumors,the generated solid tumors were similar to actual tumors,and the deterioration was higher.This research therefore acts as a foundation for the application of 3DP-7721 models in drug development research.

Studies on Antineoplastic Effect by Adjusting Ratios of Targeted-ligand and Antitumor Drug

A series of drug delivery systems based on a sodium alginate derivative were prepared by mixing glycyrrhetinic acid （GA） and doxorubicin （DOX） conjugates at different ratios. GA （a liver-targeting ligand） and DOX （an antitumor drug） were both conjugated to oligomeric glycol monomethyl ether-modified sodium alginate （ALG-mOEG） for prolonged duration of action. These NP-based delivery systems exhibited active cell uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. In addition, nanoparticles with a 1：1 （W：W） ratio of GA-ALG-mOEG and DOX-ALG-mOEG （NPs-3） showed the highest cellular uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. Specifically, when mixed nanoparticles defined as NPs-3 were injected in mice, liver DOX concentration reached 61.9 μg/g 3 h after injection, and AUC0-∞ and t1/2 of DOX in liver reached 4744.9 μg·h/g and 49.5 h, respectively. In addition, mice receiving a single injection of NPs-3 exhibited much slower tumor growth （88.37% reduction in tumor weight） 16 days after injection compared with placebo. These results indicate that effective cancer treatment may be developed using mixed NP delivery systems with appropriate ratio of targeted ligand and drug.

Effects of antibiotic antitumor drugs on nucleotide levels in cultured tumor cells:an exploratory method to distinguish the mechanisms of antitumor drug action based on targeted metabolomics

Nucleotide pools in mammalian cells change due to the influence of antitumor drugs,which may help in evaluating the drug effect and understanding the mechanism of drug action.In this study,an ion-pair RP-HPLC method was used for a simple,sensitive and simultaneous determination of the levels of 12 nucleotides in mammalian cells treated with antibiotic antitumor drugs(daunorubicin,epirubicin and dactinomycin D).Through the use of this targeted metabolomics approach to find potential biomarkers,UTP and ATP were verified to be the most appropriate biomarkers.Moreover,a holistic statistical approach was put forward to develop a model which could distinguish 4 categories of drugs with different mechanisms of action.This model can be further validated by evaluating drugs with different mechanismsof action.This targeted metabolomics study may provide a novel approach to predict the mechanism of action of antitumor drugs.

A NEW EXPERIMENTAL AND CLINICAL APPROACH OF COMBINING USAGE OF HIGHLY ACTIVE TUMOR-INFILTRATING LYMPHOCYTES AND HIGHLY SENSITIVE ANTITUMOR DRUGS FOR THE ADVANCED MALIGNANT TUMOR

In recent years, tumor-nfiltrating lymphocytes (TILs) have been reported to be effective for tumors in experimental and clinical research. In order to increase the therapeutical effect, we modified some steps of Rosenberg's approach a. cold digestion with collagenase at 4C for 24 hours; b. sedimentation instead of centrifugation; c. elimination of tumor cells before the cultivation procedure. Compared with the original approach, the proliferation, activity and cytotoxicity of TILs obtained by the modified procedure were much improved. TILs' expansion-old was greater than that with the original approach. Cytotoxicity against rumor cells was more potent. Increased TILs' subsets were CD3 and CD8 cells. Meanwhile, we took tumor cells from tumor tissues to test their in vitro chemosensitivities to different drugs in order to select highly sensitive antitumor drugs for treatment of cases with advanced tumors. According to the design of using highly active TILs and highly sensitive drugs (H & H therapy), preliminary clinical results of 50 cases showed higher response rates than those in treatment with TIL / IL2, LAK / 1L2 and TIL+IL2+CTX. Less toxic side effects were observed in 14 patients.

High-density lipoprotein as a potential carrier for delivery of a lipophilic antitumoral drug into hepatoma cells

AIM: To investigate the possibility of recombinant highdensity lipoprotein (rHDL) being a carrier for delivering antitumoral drug to hepatoma cells. METHODS: Recombinant complex of HDL and aclacinomycin (rHDL-ACM) was prepared by cosonication of apoproteins from HDL (Apo HDL) and ACM as well as phosphatidylcholine. Characteristics of the rHDL-ACM were elucidated by electrophoretic mobility, including the size of particles, morphology and entrapment efficiency. Binding activity of rHDL-ACM to human hepatoma cells was determined by competition assay in the presence of excess native HDL. The cytotoxicity of rHDL-ACM was assessed by MTT method. RESULTS: The density range of rHDL-ACM was 1.063-1.210 g/mL, and the same as that of native HDL. The purity of all rHDL-ACM preparations was more than 92%. Encapsulated efficiencies of rHDL-ACM were more than 90%. rHDL-ACM particles were typical sphere model of lipoproteins and heterogeneous in particle size. The average diameter was 31.26±5.62 nm by measure of 110 rHDL-ACM particles in the range of diameter of lipoproteins. rHDL-ACM could bind on SMMC-7721 cells, and such binding could be competed against in the presence of excess native HDL. rHDL-ACM had same binding capacity as native HDL. The cellular uptake of rHDL-ACM by SMMC-7721 hepatoma cells was significantly higher than that of free ACM at the concentration range of 0.5-10 μg/mL (P<0.01). Cytotoxicity of rHDL-ACM to SMMC-7721 cells was significantly higher than that of free ACM at concentration range of less than 5 ug/mL (P<0.01) and IC50 of rHDL-ACM was lower than IC50 of free ACM (1.68 nmol/L vs3 nmol/L). Compared to L02 hepatocytes, a normal liver cell line, the cellular uptake of rHDL-ACM by SMMC-7721 cells was significantly higher (P<0.01) and in a dose-dependent manner at the concentration range of 0.5-10 μg/mL.Cytotoxicity of the rHDL-ACM to SMMC- 7721 cells was significantly higher than that to L02 cells at concentration range of 1-7.5μg/mL (P<0.01). IC50 for SMMC-7721 cells (1.68 nmol/L) was lower than that for L02 cells (5.68 nmol/L), showing a preferential cytotoxicity of rHDL-ACM for SMMC-7721 cells. CONCLUSION: rHDL-ACM complex keeps the basic physical and biological binding properties of native HDL and shows a preferential cytotoxicity for SMMC-7721 hepatoma to normal L02 hepatocytes, HDL is a potential carrier for delivering lipophilic antitumoral drug to hepatoma cells.

Development of NAMI-A-loaded PLGA-mPEG Nanoparticles:Physicochemical Characterization, in vitro Drug Release and in vivo Antitumor Efficacy

NAMI-A[imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenium(Ⅲ)] shows extraordinary activities against metastatic tumors. However, the hydrolysis of NAMI-A to produce dimethyl sulfoxide(DMSO) could reduce anti-metastatic activity. To enhance the circulation time and the anti-metastatic effect of NAMI-A, NAMI-A-loaded nanoparticles were prepared by the double emulsion method and characterized by scanning electron microscopy for surface morphology, laser light scattering for size and zeta potential for surface charges. Controlled release of NAMI-A was observed in a sustained manner. Compared with free NAMI-A, NAMI-A-loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth in T739 mice. PLGA-mPEG nanoparticles are promising for further studies as drug delivery carriers.

信息系统辅助抗肿瘤药物处方审核分析

目的 分析信息系统辅助抗肿瘤药物处方及医嘱审核的问题,针对性完善审核规则,为提高抗肿瘤药物处方审核的质量提供参考。方法 收集四川省肿瘤医院2020—2022年信息系统辅助抗肿瘤药物处方及医嘱审核的问题,数据来源于医院美康合理用药监测系统(PASS),由临床药师对相关问题进行点评,对点评结果及相关问题进行分析。结果 共收集抗肿瘤药物处方审核问题9 325条,其中门诊处方6 279条(67.3%),住院医嘱3 046条(32.7%);适应证不适宜6 153条(66.0%),药物禁忌证1 933条(20.7%),给药途径不适宜449条(4.8%),药品配伍不适宜345条(3.7%),用药频次不适宜177条(1.9%),用药人群不适宜133条(1.4%),单次剂量不适宜74条(0.8%),药物相互作用不适宜39条(0.4%),药品总量不适宜22条(0.2%)。临床药师点评结果为合理的4 459条,假阳性率为47.8%,假阳性问题包括:适应证不适宜2 264条(50.8%),药物禁忌证1 933条(43.3%),给药途径不适宜231条(5.2%),用药人群不适宜31条(0.7%)。结论 信息系统辅助抗肿瘤药物处方审核可有效拦截不合理用药问题,提升处方和医嘱的审核质量,但抗肿瘤药物循证医学证据更新快,药师应结合最新的循证医学证据,不断维护和完善审方规则。

依鲁替尼(Ibrutinib)合成路线图解

依鲁替尼(Ibrutinib)是一款由Pharmacyclics和Janssen Biotech公司联合研发的布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase,BTK)抑制剂,也是第一个BTK靶向治疗套细胞淋巴癌(MCL)的小分子药物.本文对依鲁替尼的合成工艺进行归纳总结,以期为依鲁替尼的合成路线设计提供新思路.

抗肿瘤药物不良反应风险预警模块的设计与构建

目的依托苏州大学附属张家港医院移动药师工作站,设计与构建抗肿瘤药物不良反应风险预警模块。方法建立监测药物目录、抗肿瘤药物不良反应知识库,基于移动药师工作站合理用药智能管理系统加入抗肿瘤药物不良反应风险预警模块,迅速、精准抓取实验室数据、病程描述,发现异常指标,对临床药师工作站发起提醒。结果在移动药师工作站植入抗肿瘤药物不良反应的风险预警模块,解决了临床药师不良反应监测工作量大、专业性要求高、易漏判的弊端,帮助临床医师和护理人员及时获取患者不良反应信息,以便密切做好临床观察和随访。结论本工作站建立的抗肿瘤药物不良反应风险预警模块,有助于提高不良反应快速响应能力,具有临床推广价值。

某院静脉用药调配中心抗肿瘤药物不合理医嘱评价结果分析

目的探讨某院静脉用药调配中心抗肿瘤药物不合理医嘱的原因,根据不合理的原因制定个性化的对策,规范患者合理、安全用药。方法收集某院2023年静脉用药调配中心抗肿瘤药物不合理医嘱的记录共258条,统计这些不合理医嘱的药物种类、科室分布,以及记录不合理医嘱的原因,并采取针对性的措施,减少不合理医嘱。结果统计分析显示,某院2023年静脉用药调配中心抗肿瘤药物不合理医嘱共258张,其中放疗科、肿瘤科、胸外科的不合理医嘱比率占前三位,分别为32.17%、21.71%、20.16%;不合理类型中溶媒选择不合理的占比最高,为43.41%,其次分别为溶媒用量、浓度不合理,用药剂量不合理,用药顺序不合理,配伍不当,其他,占比分别为29.07%、15.50%、5.04%、4.26%、2.71%。112张抗肿瘤药物溶媒选择不合理医嘱中,注射用依托泊苷溶媒选择不合理最多,占比为33.04%。75张抗肿瘤药物溶媒用量、浓度不合理医嘱中,注射用吉西他滨溶媒用量、浓度不合理最多,占比为24.00%。40张抗肿瘤药物用药剂量不合理医嘱中,复方苦参注射液超量使用最多,占比为40.00%。结论评价静脉用药调配中心抗肿瘤药物不合理医嘱发生具体原因,加强合理用药管理,采取针对性的措施,可保障抗肿瘤药物合理应用。

微乳头型肺腺癌类器官的构建及其靶向药物的筛选

目的建立微乳头型肺腺癌类器官的培养方法,并开展靶向药物的筛选。方法自确诊为微乳头型肺腺癌患者手术组织样本中提取和培养原代肺癌类器官,动态观察和记录肺癌类器官生长情况;苏木精-伊红(HE)染色法及免疫组化染色法比较肺癌类器官与亲本组织间肿瘤细胞形态及蛋白表达特征;实时荧光定量聚核酶链反应检测肺癌亲本组织和类器官中基因突变情况;基于基因检测结果挑选靶向药物并验证其体外抑瘤效果。结果成功从微乳头型肺腺癌组织中培养出类球形肿瘤类器官,可传代至少3代。HE染色结果可见类器官中肿瘤细胞形态与亲本组织细胞基本一致;免疫组化染色结果显示肺癌类器官与亲本组织中各基因的蛋白表达水平大致相同;基因突变分析结果显示,肺癌亲本组织和类器官的突变基因结果一致,均体现为原癌基因酪氨酸蛋白激酶受体Ret(RET)融合突变。基于肺癌类器官的靶向药物筛选结果显示,凡德他尼的体外抑瘤效果最佳。结论基于微乳头型肺腺癌类器官的药筛实验可在短时间内筛选出高效靶向药物,可使微乳头型肺腺癌患者从中获益。

医院静脉用药调配中心抗肿瘤药物配置的精益管理

目的研究分析精益管理在医院静脉用药调配中心(Pharmacy Intravenous Admixture Services,PIVAS)抗肿瘤药物配置中的应用效果。方法选取2022年1月—2023年12月滨州市中心医院PIVAS的22名抗肿瘤药物配置工作人员作为研究对象,按照时间的不同,设为对照组(实施常规管理,2022年1—12月)和观察组(实施精益管理,2023年1—12月)。对比分析两组的管理效果。结果观察组的审方、配置、排药时间均短于对照组,差异有统计学意义(P均<0.05)。观察组药物配置环节差错发生率比对照组低,差异有统计学意义(P均<0.05)。观察组的总满意度高于对照组,差异有统计学意义(P<0.05)。结论在PIVAS抗肿瘤药物配置中,采取精益管理能够获取良好效益,可有效提升药物配置质量,同时能够有效减少差错事件发生,为临床抗肿瘤药物的合理用药提供了保障。

靶向血小板的抗肿瘤药物研究进展

血小板长期以来一直被认为是止血和血栓形成的关键参与者;然而,越来越多的证据表明,它们也与癌症有关。临床前和临床研究表明,血小板可以通过血小板和癌细胞之间的各种串扰来促进肿瘤发生和转移。血小板在肿瘤发生的各个阶段,包括肿瘤生长、肿瘤细胞外渗和转移中都发挥着积极的作用。此外,癌症患者的血小板增多与患者不良生存率相关。由于大量的微粒和外泌体,血小板还能够很好地协调局部和远处的肿瘤-宿主之间的相互作用。因此,以血小板为靶点的抗肿瘤药物具有很大的开发与应用前景。以下将对靶向血小板的抗肿瘤药物研究进展进行综述。

抗肿瘤药物对慢性放射性肠损伤影响的病理学研究

目的从病理学角度探讨抗肿瘤药物对宫颈癌慢性放射性肠损伤组织的影响。方法回顾性分析2016年8月至2023年4月期间安徽医科大学第一附属医院宫颈癌慢性放射性肠损伤患者的临床病理资料。根据RTOG/EORTC评分标准对49例患者的放射性肠损伤临床症状进行评分和严重程度分级。根据药物治疗方案分为抗血管生成药物治疗组和无抗血管生成药物治疗组,紫杉类药物化疗组和无紫杉类药物化疗组。采用病理学半定量评分系统评估患者的慢性放射性肠损伤程度,分别比较对应亚组间微血管计数、狭窄血管计数、狭窄血管比例、病理总分、溃疡、炎症、水肿、坏死和纤维化指标的差异。并使用Cox分析慢性放射性肠损伤患者发生严重并发症的独立危险因素。结果抗血管生成药物治疗组的狭窄血管计数、狭窄血管比例、溃疡和炎症程度均高于无抗血管生成药物治疗组,差异有统计学意义(P均<0.05);而抗血管生成药物治疗组的微血管计数和纤维化程度均低于无抗血管生成药物治疗组,差异有统计学意义(P均<0.05)。紫杉类药物化疗组与无紫杉类药物化疗组间的病理学指标比较,差异无统计学意义(P均>0.05)。Cox多因素分析显示,抗血管生成药物不是慢性放射性肠损伤患者发生严重并发症的独立危险因素(P>0.05)。结论抗血管生成药物加重了宫颈癌慢性放射性肠损伤组织的血管狭窄、溃疡和炎症,但减轻了纤维化。紫杉类药物对宫颈癌慢性放射性肠损伤组织无明显影响。

近5年国家谈判的抗肿瘤药纳入医保的品种及适应症变化分析

目的统计2019年到2023年五版国家医保目录协议期内谈判的抗肿瘤药品种的变化及医保限定的支付病种范围的变更,重点对单克隆抗体和蛋白激酶抑制剂的部分特殊品种的适应症变化进行分析。方法以表格的形式罗列出五版国家医保目录协议期内谈判的各类抗肿瘤药的品种个数、纳入年份及医保限定的支付病种范围。结果五版国家医保目录中协议期内谈判的抗肿瘤药的品种总数呈逐年递增趋势,各类抗肿瘤药的品种数排前3位的均是蛋白激酶抑制剂、单克隆抗体、其他类抗肿瘤药。医保限定的支付病种涵盖各个系统的肿瘤,如呼吸系统、消化系统、血液系统、泌尿系统、乳腺等,其中呼吸系统所占比例最高。部分品种连续5年均进入国家谈判药品目录。结论传统的抗肿瘤药由于不良反应大,患者无法耐受,近年来已逐渐被新型抗肿瘤药所替代。但由于新型抗肿瘤药价格昂贵,患者又需要长时间使用,故需要国家干预,尽可能降低价格,方能满足肿瘤患者的用药需求和可及性,从而减轻经济负担,提高生活质量。