Application of Real-World Evidence in the Approval of Antitumor Drugs

Objective To study the information of real-world evidence(RWE)that can make up the deficiency of RCT results,the unfeasibility of some trials and the possible ethical problems,and to promote the approval of RWE for anti-tumor drugs.Methods Literature analysis,policy analysis and comparative analysis were used.Results and Conclusion The studies and application of RWE in the United States,the European Union,and China were reviewed.The approval of anti-tumor drugs supported by RWE was generally used for external control groups in single arm trials,clinical efficacy and safety of adjuvant support drugs,or background analysis.The types of approvals included innovative anti-tumor drugs,supplemented indications of the approved drugs,expanding patient population,and combination medication.This study can provide reference for the approval of anti-tumor drugs using RWE in China.It is recommended to combine traditional RCT with RWE to promote the approval of anti-tumor drugs.

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.

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.

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.

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.

Conformation and Antitumor Activity of Novel Metal Complexes of Piperazinedithioformates

The in vitro antitumour efficacy of some novel metal complexes of piperazinedi thioformates （SR-M） was examined in six cancer cell lines. The activity was compared with that of piperazinedithioformates. Biological evaluations of a series of SR-M compounds suggest that the compounds 1 c （SR-Cu） and If （SR-Sn） show a potent antitumor activity. The stable conformation structure of SR-Cu as a representative of SR-M was investigated and confirmed by computer workshop.

THE ANTITUMOR ACTIVITIES OF GNIDIMACRIN ISOLATED FROM STELLERA CHAMAEJASMEL．

Gnidimacrin, a diterpene compound, isolated from the methanol extract of Stellera, chamaejasme L., showed significant antitumor activities against mouse leukemia P-388 and L-1210 in vivo, such as Lewis lung carcinoma, B-16 melanoma and Colon cancer 26. It showed ILSs of 40%.49% and 41% at the dosages of 0.01-0.02 mg/kg ip,respectively. Gnidimacrin strongly inhibited cell Proliferation of human cancer cell lines such as leukemia K562, stomach cancers Kato-III, MKN-28, MKN-45, and mouse leukemia L-1210 by the MTT assay and colony forming assay in vitro. The IC50 of gnidimacrin was 0.007-0.00012 μg/ml. It is concluded that gnidimacrin is the principal antitumor element in Stellera chemaejasme L. with strong antitumor activities.

A New Biological Strategy for Drug Delivery: Eucaryotic Cell-Derived Nanovesicles

An efficient drug delivery is the prerequisite of the successful chemotherapeutic treatments of many human diseases. Despite a great number of approaches, the improvement of drug cell internalization remains an actual research challenge. We propose a new biological delivery system based on the extracellular vesicles released by a non-pathological eukaryotic microorganism, Dictyostelium discoideum. After a summary of the main characteristics of these extracellular vesicles, including of their lipid bilayer that appears as a good candidate for initiating membrane fusion, followed by delivery of their encapsulated drug, the capacity of these vesicles to convey drugs into human cells was demonstrated in vitro on two tumor cell lines, resistant leukaemia K562r and cervix carcinoma HeLa cells. A comparison with other extracellular vesicles, like exosomes or bacteria-derived particles, stresses the unique properties of Dictyostelium extracellular nanovesicles for drug delivery.

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。

Synthesis and Antitumor Activity of Poly-L-Lysine Containing 5-Fluorouracil as Pendent Group

Homopolymers of L-amino acids such as poly(L-glutamic acid) and poly (Llysine) not only have good biocompatibility and biodegradability, but also lack of immunogenicity. It has been reported that homopoly(L-amino acids) were used as the carriers of antitumor drugs such as mustard, methotrexate (MTX), cyclophosphamide, daunomycin(DM) and adriamycin (ADR). 5-Fluorouracil(5-FU) is most useful for the treatment of patients with carcinoma of the breast and gastrointestinal

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。