Research progress of sphingosine kinase and sphingosine-1-phosphate (S1P) /S1P receptor signaling in tumor microenvironment / 药学学报

Sphingosine kinase (SphK), sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) are involved in the tumor biological processes such as tumor cell proliferation and migration, and play an important role in the development of cancer. In recent years, researchers have increasingly focused on the interaction between cancer cells and the tumor microenvironment. The tumor microenvironment is genetically stable and can be induced to an antitumor phenotype, which has significant therapeutic advantages. Studies have shown that SphK/S1P/S1PR can regulate multiple aspects of the tumor microenvironment. This review summarizes the effects of SphK and S1P/S1PR signaling on the tumor microenvironment from four perspectives: tumor immune microenvironment, cancer associated fibroblasts, tumor angiogenesis and tumor hypoxic microenvironment, and also outlines potential drug research related to these signal molecules, aiming to elucidate the role of SphK/S1P/S1PR in tumor occurrence and development and provide new ideas for the research of anti-tumor drugs.

Research progress on cardiovascular toxicity associated with anti-tumor drugs and its prevention and treatment / 药学学报

Cancer and cardiovascular diseases are the two major causes of death worldwide. The application of anti-tumor drugs has significantly improved the prognosis of patients, the cardiovascular toxicity caused by the application of them has become an important factor affecting the survival and prognosis of cancer patients. Therefore, the prevention and treatment of cardiovascular toxicity related to cancer treatment is increasingly important. The cardiovascular toxicity associated with anti-tumor drugs exhibits different clinical manifestations and involves multiple pathological mechanisms. This article reviews the current research progress from the perspective of the characteristics, molecular mechanisms and prevention and treatment strategies of cardiovascular toxicity caused by cancer drugs.

Research progress on anti-tumor and tumor immunity of marine natural products / 药学学报

In recent years, the oceans have provided an important source of highly promising new anti-tumor drugs for innovation and screening, with approximately 56% of biologically active compounds being discovered to have anti-tumor effects each year. In this study, we classified and summarized the approved drugs of marine origin in terms of anti-tumor therapy, and firstly, we briefly overviewed the role of the immune system in cancer pathogenesis and discussed the current dilemma of cancer immunotherapy and highlighted the main anti-tumor targets of marine drugs. Further, with a focus on tumor immunity, we classified and outlined the history of currently approved marine original drugs by species origin, structural features, relevant pathways, and clinical application and therapy. Lastly, the limitations of current marine drug research were discussed, as well as prospects and trends in new drug development.

Rethinking the marketing strategy of anti-tumor drugs by single-arm trials supported / 中华肿瘤杂志

Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.

Considerations on Clinical Development and Regulatory of the Oversea License-in Anti-tumor Drugs / 中国肺癌杂志

With the boom of China's innovative pharmaceutical industry, licensing-in model has gradually become an important research and development model for innovative pharmaceutical companies. The in-licensed drugs at different stages need different research and development (R&D) strategy in China. The pharmaceutical companies take the responsibility to comprehensively collate the oversea clinical data and conduct a detailed analysis of clinical pharmacology, safety, efficacy and ethnic sensitivity. Clinical R&D strategy should be made based on the results of the above data and analysis. We encourage high-quality drugs which fill unmet clinical needs licensed in, and as early as possible, so as to conduct multi-regional clinical trials (MRCTs). The clinical R&D strategy in China is particularly important for the drug's approval. Guidelines published by the National Medical Products Administration (NMPA) and clinical associations should be followed. Communications about clinical R&D strategy with Center of Drug Evaluation (CDE) are encouraged.
.

Research progress on pharmacokinetics and toxicity of vinorelbine / 中国药房

Vinorelbine（NVB）is a semisynthetic vinca alkaloid and can play an anti-tumor role by inhibiting the synthesis of tubulin. Its oral preparation has been used in the treatment of a variety of tumors as its convenience and good clinical response. The blood concentration of NVB is closely related to its curative effect and toxicity. Small variations in blood concentration may reduce the curative effect and even produce serious toxicity. There are some risks in the clinical drug use due to limited clinical data and effective pharmacodynamic monitoring methods. By reviewing the relevant literature at home and abroad ，this paper summarizes the research progress of in vivo pharmacokinetics and toxicity of NVB ，fully understands the pharmacokinetic characteristics and influencing factors of NVB ，the influencing factors of toxicity ，and the application status of pharmacokinetics in the adjustment of administration scheme ，so as to provide reference for its clinical rational use.

Methodological study of rapid health technology assessment of drugs ：taking antitumor drugs as an example / 中国药房

OBJECT IVE To develop a rapid health technology assessment （rHTA）methodology of drugs based on evidence integration and value judgment ，which is suitable for China ’s national conditions. METHODS The literature review was adopted to study health technology assessment （HTA）and multi-criteria decision analysis （MCDA），and then rHTA method based on China ’s condition was formulated preliminarily with anti-tumor drugs ；the method of rHTA was demonstrated by expert consultation ； finally，the feasibility of rHTA was preliminarily verified taking the drugs for the treatment of non-small cell lung cancer as an example. RESULTS Established rHTA method combined the theory and principles of HTA and MCDA ：HTA method was used to guide the collection and synthesis of literature and real-world evidence ，while MCDA made the value measurements of achievable evidences by various stakeholders from different views ；it established the working process ，evaluation dimensions ，evaluation indicators and scoring system of rHTA. The feasibility of this method was verified by the drug example of treating non-small cell lung cancer. CONCLUSIONS A set of drug-driven rHTA methodology guidance based on HTA and MCDA is established. It can quickly collect and integrate evidence ，and provide evidence support for decision makers in a short time.

A living cell-based fluorescent reporter for high-throughput screening of anti-tumor drugs / 药物分析学报

Suppression of cellular O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) can repress prolifera-tion and migration of various cancer cells,which opens a new avenue for cancer therapy.Based on the regulation of insulin gene transcription,we designed a cell-based fluorescent reporter capable of sensing cellular O-GlcNAcylation in HEK293T cells.The fluorescent reporter mainly consists of a reporter (green fluorescent protein (GFP)),an internal reference (red fluorescent protein),and an operator (neuronal differentiation 1),which serves as a "sweet switch" to control GFP expression in response to cellular O-GlcNAcylation changes.The fluorescent reporter can efficiently sense reduced levels of cellular O-GlcNAcylation in several cell lines.Using the fluorescent reporter,we screened 120 natural products and obtained one compound,sesamin,which could markedly inhibit protein O-GlcNAcylation in HeLa and human colorectal carcinoma-116 cells and repress their migration in vitro.Altogether,the present study demonstrated the development of a novel strategy for anti-tumor drug screening,as well as for con-ducting gene transcription studies.

Research progress in multi-targeted anti-tumor natural products / 药学学报

Natural products and their derivatives are important components of anti-tumor drugs. Currently, anti-tumor drugs derived from natural products which are in clinical practice are mainly conventional cytotoxic or molecularly targeted drugs. Their application is limited by drug-related side effects and drug resistance. Recent studies have shown that anti-tumor natural products often act on multiple targets in tumor cells and in turn interfere with multiple processes in tumorigenesis and development. As tumor is a systemic disease induced by multiple factors, multi-targeted natural products possess unique potential in tumor therapy. However, the targets and mechanisms of the discovered multi-targeted antitumor natural products remain elusive, which limits their further development and application. This review summarized the research progress in the mechanism of action, target identification, and structure optimization of multi-targeted anti-tumor natural products exemplified by a few typical compounds. The research and development of these agents have also been proposed.

Knowledge, Attitudes, and Practices (KAP) Survey on the Safety of Anti-tumor Drugs in Hospital Discharge among Hospital Pharmacist / 中国药学杂志

OBJECTIVE: To analyze the knowledge, attitude and practice of hospital pharmacists on the safety of patients with anti-tumor drugs discharged from hospitals, explore possible risk factors, and provide reference for targeted guidance and rational medication of tumor patients discharged. METHODS From March 15, 2019 to May 31, 2019, pharmacists at hospitals in 31 provinces (cities) in China conducted a questionnaire survey on the safety of patients with anti-tumor drugs discharged from hospitals. RESULTS: The average score of pharmacists′ knowledges of anti-tumor drugs was 46.7, equivalent to 51.8% of the total score. Most pharmacists (74.5%) are aware of the risks of discharge of antineoplastic agents and are willing (93.9%) to provide medication guidance for cancer patients. However, the pharmacists′ guidance for patients with cancer on the discharge was mostly limited to oral presentation (62.1%), and the accessibility of pharmacists to cancer patients after discharge was generally low (55.6%). CONCLUSION: Drug safety participants pay insufficient attention to the safety risks of patients with anticancer drugs discharged, and hospital pharmacists′ knowledge reserve of anti-tumor drugs has shortcomings, there is no perfect system of medication education for discharged patients, which are all risk factors threatening the safety of medication for cancer patients after discharge. Serious efforts should be made to find solutions to continuously improve the safety of patients with anticancer drugs discharged from hospitals.

Progress in molecularly targeted anti-tumor drugs derived from natural products or their derivatives / 药学学报

Conventional chemotherapy drugs, molecularly targeted drugs, and immune checkpoint inhibitors are the major constituents of anti-tumor drugs in clinical settings at present. Molecularly targeted drugs specifically target the key proteins, genes, or signal transduction pathways in tumor cells which are essential for initiation and development of tumor, resulting in selective activity to induce cell death or growth inhibition. Molecularly targeted drugs have emerged as the mainstream in the research and development of anti-tumor drugs due to its high selectivity and low toxicity. Natural products refer to the chemical constituents or metabolites originated animals, plants, or microorganisms, which have been recognized as one of the important sources of drug discovery with abundant resources and diversified structures. At present, a number of molecularly targeted anti-tumor drugs derived from natural products or their derivatives have been approved for cancer therapy or in clinical trials. This review will summarize the molecularly targeted anti-tumor drugs derived from natural products or their derivatives according to their different cellular targets, and also outline the molecular mechanism, progress, and perspectives of these drugs.

Application of DrugAbacus Method in Pricing Antitumor Drugs / 中国药学杂志

OBJECTIVE: China is still in its infancy in assessing the value of anti-tumor drugs, lacking a mature drug value assessment system. To provide reference for the establishment of a pharmacoeconomic model based on value assessment in China, and provide valuable reference for clinicians and patients to choose treatment options, Through the analysis and discussion of the DrugAbacus interactive calculator. METHODS: The value components and data sources of the DrugAbacus interactive calculator were analyzed by literature search, data query, etc., and the price of the anti-tumor drugs was evaluated according to the baseline values. RESULTS: The actual price of anti-cancer drug afinitor is higher than the recommended price when used to treat kidney cancer, pancreatic cancer and breast cancer. When the anti-tumor drug avastin is used in the treatment of colon cancer, the actual price is not much different from the recommended price. Halaven's suggested price is always higher than the actual price, that is, the price of the drug is at least reasonable or even low, and Ixempra's price is high, so using the drug Halaven can save more money than using the drug Ixempra. CONCLUSION: The DrugAbacus method provides a complex analysis of the factors that should be considered in drug pricing. Although there are limitations, this method reflects to a large extent the evaluation of the value of innovative drugs in society, which can provide reference for drug pricing in China.

Research Progress on Stimuli-responsive Polymer-drug Conjugates for Anti-tumor Drugs Delivery / 中国药学杂志

Polymer-drug conjugates (PDCs) have been extensively studied as nanocarriers for anti-tumor drugs delivery due to excellent stability in circulation and high drug loading ability. Stimuli-responsive PDCs(SRPDCs) could release the loading drug in response to various intra-or extracellular biological stimulis (eg, acidic pH, altered redox potential, and upregulated enzyme), as well as external artificial stimulis (eg, magnetic feld, light, temperature, and ultrasound), which are considered as "smart" nanocarriers for delivery of anti-tumor drugs. In this article, recent progresses in the development of SRPDCs for cancer therapy are reviewed, covering the design, smart linkages as well as responsive drug release property, so as to provide reference for the development of related drug delivery systems. In order to improve the successful translation of stimuli-responsive PDCs, drawbacks and limitations of current researches are discussed, besides, future perspectives and research strategies are also provided.

Progress in the mechanisms of anticancer peptides / 生物工程学报

In recent years, cancer has become a major concern in relation to human morbidity and mortality. Anticancer peptides (ACPs) are the bioactive peptide with antitumor activity and found in many organisms, including mammals, amphibians, insects, plants and microorganisms. ACPs have been suggested as promising agents for antitumor therapy due to their numerous advantages over traditional chemical agents such as low molecular masses, relatively simple structures, greater tumor selectivity, fewer adverse reactions, ease of absorption, a variety of routes of administration and low risk for inducing multi-drug resistance. Combining with the related research in our group, we summarized the mechanisms of ACPs to provide some directions for research and development of peptide-based anticancer drugs.

Enzymatic synthesis of three kinds of galactose-cholesterol ligands and their structure-activity relationship with liver targeting / 中草药

Objective To construct three kinds of doxorubicin liposomes modified with cholesterol-galactose ligand by lipase-catalyzed method and compare their characteristic of pharmacokinetics and tissue distribution in vivo. Methods Three types of cholesterol-galactose ligands, CHS-C8-GalNAc, CHS-C8-GAL, and CHS-C8-LA were synthetized by lipase-catalyzed method in nonaqueous phase. The structure characterizations of products were obtained by MS and NMR. Conventional liposomes (CL DOX) and ligand-coupled liposomes (NGal-LP DOX, Gal-LP DOX, and LA-LP DOX) were prepared by thin film dispersion-ammonium sulphate gradient method. Structure-activity relationship between asialoglycoprotein receptor (ASGPr) and the chemical structure of the glycolipids was explored through the pharmacokinetics and tissue distribution parameters of ligand-coupled liposomes in vivo. Results The desired compounds with a high yield of above 90% were confirmed by MS and NMR. The liposomes average size was lower than 90 nm, polymer dispersity index was lower than 0.1, encapsulation efficiency was greater than 99%, leakage rat was lower than 5% with 24 h, and zeta potential closed to zero. The affinity of the three ligand molecules to liver was the following order: CHS-C8-GalNAc > CHS-C8-LA > CHS-C8-Gal. However, only the liposomes modified with CHS-C8-GalNAc could significantly be inhibited by the preinjection of asialofetuin for hepatic uptake rate (P 0.05). Conclusion The ligand with N-acetylgalactosamine residue showed high targeting efficiency for hepatocytes, while the ligand with D-galactose (Gal) or lactitol residue could competitive bind with Gal particle receptor on kupffer cells.

Study on Preparation of Anti-tumor Drug H6 Polymeric Micelles and Their in vitro Anti-tumor Effects / 中国药房

OBJECTIVE:To prepare anti-tumor drug H6(lactone compound)polymeric micelles,and to investigate its in vitro anti-tumor effects. METHODS:Using mPEG2000-PCL4000 as carrier,H6/mPEG2000-PCL4000 micelles were prepared. Using particle size, PDI and 48 h whether to produce precipitation as indexes,feeding ratio,H6 concentration,volume ratio of organic solvent were screened. The encapsulation efficiency and drug-loading amount of micelle were all detected. MTT assay was used to detect the tox-icity of micelles and H6 solution to human non-small cell lung cancer cell A549 and human lung cancer cell H460. RESULTS:The screened formulation was as follows as feeding ratio of 1∶25,H6 concentration of 2 mg/mL,the ratio of ethanol to chloroform of 1∶1(V/V). The parameters of prepared H6/mPEG2000-PCL4000 micelles were as follows as particle size of(40.74±0.116 3)nm,PDI of(0.101±0.006),encapsulation efficiency of(94.87±0.016 3)%,drug-loading amount of(7.07±0.001 5)%(n=3). IC50 of mi-celles and H6 solution to A549 cell were 15.62 and 12.57 nmol/L;IC50 of micelles and H6 solution to H460 cell were 27.68 and 15.19 nmol/L. CONCLUSIONS:H6/mPEG2000-PCL4000 micelles are prepared successfully and show in vitro anti-tumor effects.

Pharmaceutical Care for One Case of Allergic Reactions Caused by Oxaliplatin / 中国药房

OBJECTIVE:To explore the role of clinical pharmacists on pharmaceutical care for allergic reaction caused by ox-aliplatin. METHODS:Clinical pharmacists conducted pharmaceutical care for a patient with oxaliplatin-induced allergic reaction, and suggested stopping taking oxaliplatin,giving Dexamethasone injection 5 mg and then slowing down injection speed. RE-SULTS:Physicians adopted the suggestions of clinical pharmacists. Allergic reaction relieved 5 min after giving Dexamethasone in-jection. The patient didn't suffered from this allergic reaction again under tight supervision. CONCLUSIONS:Oxaliplatin is often used for tumor therapy. Medical staff should be familiar with the prevention,diagnosis and treatment of ADR,evaluate oxaliplatin chemotherapy plan in advance and screen high risk allergy factor. The participation of clinical pharmacists in pharmaceutical care contribute to ADR monitoring and promote safe and rational drug use in the clinic.

Advances in inhibitors of MDM2 and MDM4 / 中国药科大学学报

@#The protein p53 plays an important role in the regulation of DNA repair, cell cycle arrest, apoptosis, senescence, autophagy and metabolism. MDM2 and MDM4 are the key negative regulatory proteins of p53. Inhibition of MDM2 and MDM4 has become a research hotspot in cancer therapy. Currently, seven MDM2 inhibitors(RG7112, MI-77301, RG7388, AMG232, CGM097, MK-8242, DS-3032b)and one MDM2/MDM4 dual inhibitor(ALRN-6924)have entered clinical trials. This paper highlights small molecule discovery, pharmacological activities and clinical research advances of MDM2 inhibitors in clinical trials, in addition, this review introduces research advances of MDM2/MDM4 dual inhibitors.

Research progress on irreversible tyrosine kinase inhibitors / 中国药理学通报

Dysfunction in tyrosine kinase activity disrupts the nor-mal control of cellular phosphorylation signaling pathways,which plays a vital role in genesis and development of various tumors, and makes tyrosine kinases a class of targets of many anti-tumor drugs. Currently most approved tyrosine kinase inhibitors ( TKIs) are based on irreversible binding mechanisms, making them poorly selective, not potent or sustained enough regarding pharmacological effects and prone to triggering resistance. In the past decade, much progress has been made in the development of a new class of TKIs which irreversibly inhibit their target proteins via the formation of covalent bonds, overcoming the drawbacks of irreversible TKIs. Several irreversible TKIs have entered markets or clinical research phases. This review is to summarize the structural, pharmacological and medicinal chemical properties of investigational and marketed irreversible TKIs as well as their re-cent developments.