Review of Development of Emerging Clinical Antitumor Therapeutics / 肿瘤防治研究

With the continuous progress of tumor treatment methods in recent years, more and more emerging antitumor drugs have been approved to market and put into clinical use. In addition, some treatments that are in clinical trials such as gene therapy are also continuously making new breakthroughs. In this review, we mainly give a brief introduction to the novel antineoplastic therapies that have been clinically used in recent years, as well as the ones with remarkable efficacy and are expected to be approved for marketing.

In silico evaluation of potential drugs for the treatment of Colorectal Carcinoma

Abstract To evaluate possible new drugs for the treatment of Colorectal Carcinoma (CRC) using in silico tools was the main objective of this study. The method of analysis used was the in silico evaluation of tumor markers and their interaction with selected drugs, through the study of its pharmacokinetic and pharmacodynamic characteristics. A potential therapeutic target pointed out in this study was the Cell Division Cycle 25 B (CDC25B), belonging to the CDC25 phosphatase family. Overexpression of CDC25 phosphatases is often associated with a wide variety of cancers. In addition, CDC25B is an oncogenic protein that induces neoplastic transformation. In CRC, CDC25B is overexpressed to activate the CDC2/cyclin B complex and improve the growth and survival of these tumors. Four drugs were identified for evaluation, with α-amyrin being selected for docking, because it was that had the best characteristics according to the methodology used. The α-amyrin ligand obtained the interaction energy value of -7.6 G (Kcal/mol), while the standard CDC25B ligand obtained -10.0 G (Kcal/mol). TThe results showed that the CDC25B protein was the only structure cocrystallized with α-amyrin and presented favorable outcomes in docking, being a candidate for further studies for its use in the CRC targeted therapy

Effectiveness of a Camera Support System for the Prevention of Occupational Anti-cancer Drug Exposure / 社会薬学

During the preparation of anti-cancer drugs, mutual verification with another pharmacist is performed to prevent preparation mistakes. In a small-to-medium sized hospital with relatively few pharmacists, it is common for nurses to perform verifications. The nurses approach the safety cabinet only lightly protected by their clothing. Thus, occupational exposure to anti-cancer drugs, which are hazard drugs is a concern. To prevent occupational exposure, we implemented and investigated the effectiveness of an “anti-cancer drug preparation camera support system”, which allowed two-way communication and video recording between an anti-cancer drug preparation room and a pharmacy preparation room at different locations. The amount of exposure to anti-cancer drugs was defined as the time required to verify the anti-cancer drug. The average daily exposure time was calculated based on the number of verifications and the average time for each verification. This value was then compared with the exposure time when the camera system was implemented. In addition, the frequency of work interruption when a pharmacist verified, after the introduction, was assessed. The effectiveness of the camera supported system was validated, the verification time for anti-cancer drugs was reduced from 48.9±9.3 minutes/day to 4.4±0.9 minutes/day. This means that the occupational exposure time of 48.9±9.3 min/day for nurses was reduced to zero and the occupational exposure time for dispensing pharmacists was reduced to 4.4±0.9 min/day. In addition, it allowed pharmacists to properly confirm anti-cancer drugs preparations.

Assessing the Attitude of Medical Workers to Anti-Cancer Drug Exposure Measures by an Awareness Survey / 医薬品情報学

Objective: The importance of occupational exposure control in cancer therapy is widely recognized, and measurement of anti-cancer drug exposure during preparation, as well as comprehensive measures, including administrative control, patients’ excrements, and environmental pollution, among others, are becoming important. The Osaka Women’s and Children’s Hospital introduced the closed system drug transfer device (CSTD) for administering anticancer drugs, and conducted consistent exposure measures from preparation to disposal. We simultaneously conducted an awareness survey on anti-cancer drug exposure measures for health care workers,observed the changes in their awareness and behavior, and examined the issues that constantly challenge anti-cancer drug exposure measures.Method: We surveyed doctors, nurses, and pharmacists who handle anticancer drugs belonging to the Osaka Women’s and Children’s Hospital from March 2018 to October 2018. The questionnaire was anonymous and was collected within one week after distribution. In the questionnaire survey, we obtained permission to present the contents on paper and orally.Results: The questionnaire response rate was approximately 70%. Following the training and introduction sessions, the participants had an improved understanding of Hazardous Drugs and CSTD. The introduction of the workshops on anti-cancer drug exposure measures and CSTD encouraged the nurses to reflect on the exposure measures and revisit the manuals on in-hospital treatment with anti-cancer drugs; however, there was little or no change in the behavior of the pharmacists.Discussion: Since nurses work primarily in the field of patient care, their awareness of anti-cancer drugs has gradually declined, and it was observed that procedures for exposure control were not being followed. In order to ensure that anti-cancer drug exposure measures are properly observed, pharmacists need to take initiatives and conduct in-hospital workshops once every six months. It is also necessary to educate the medical staff about electronic devices in order to ensure their easy participation in workshops and encourage e-learning.

Advances in small molecule inhibitors of ACK1 / 药学学报

ACK1 (activated Cdc42-associated kinase) is a non-receptor tyrosine kinase, originally identified by its binding to the GTP-binding small GTPase Cdc42. It is widely expressed in human tissues and activated by various extracellular growth factors such as EGF, PDGF and TGF-β. The activated ACK1 mediates the signaling cascade by interacting with downstream effectors followed by their phosphorylation. In recent years, researchers have investigated the biological functions of ACK1 and its roles in cancer research. The gene amplification and overexpression of ACK1 is associated with a poor prognosis and metastasis in a variety of cancers including lung, ovarian and prostate cancers. Therefore, the development of small molecule inhibitors of ACK1 provides promising opportunities for cancer-targeted therapy. In this review, we briefly describe recent advances in understanding the activation and biological function of ACK1 and introduce its novel inhibitors with potential therapeutic activities in preclinical studies.

Construction of Tumor Tissue Array on An Open-Access Microfluidic Chip / 分析化学

An open-access microfluidic chip which enabled automatic cell distribution and complex multi-step operations was developed.The microfluidic chip featured a key structure in which a nanoporous membrane was sandwiched by a cell culture chamber array layer and a corresponding media reservoir array layer.The microfluidic approach took advantage of the characteristics of the nanoporous membrane.On one side, this membrane permitted the flow of air but not liquid, thus acting as a flow-stop valve to enable automatic cell distribution.On the other side, it allowed diffusion-based media exchange and thus, mimicked the endothelial layer.In synergy with a liquid transferring platform, the open-access microfluidic system enabled complex multi-step operations involving medium exchange, drug treatment, and cell viability testing.By using this microfluidic protocol, a 10 × 10 tissue arrays was constructed in 90 s, followed by schedule-dependent drug testing.Morphological and immunohistochemical assays results indicated that the resultant tumor tissue was faithful to that in vivo.Drug testing assays showed that the microfluidic tissue array promised multi-step cell assays under biomimetic microenvironment, thus providing an advantageous tool for cell research.

Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

Hypoxia is frequently observed in solid tumors and also one of the major obstacles for effective cancer therapies. Cancer cells take advantage of their ability to adapt hypoxia to initiate a special transcriptional program that renders them more aggressive biological behaviors. Hypoxia-inducible factors (HIFs) are the key factors that control hypoxia-inducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. HIFs, mainly HIF-1 and -2, have become potential targets for developing novel cancer therapeutics. This article reviews the updated information in tumor HIF pathways, particularly recent advances in the development of HIF inhibitors. These inhibitors interfere with mRNA expression, protein synthesis, protein degradation and dimerization, DNA binding and transcriptional activity of HIF-1 and -2, or both. Despite efforts in the past two decades, no agents directly inhibiting HIFs have been approved for treating cancer patients. By analyzing results of the published reports, we put the perspectives at the end of the article. The therapeutic efficacy of HIF inhibitors may be improved if more efforts are devoted on developing agents that are able to simultaneously target HIF-1 and -2, increasing the penetrating capacity of HIF inhibitors, and selecting suitable patient subpopulations for clinical trials.

Risk evaluation and mitigation strategy in oncology products / 中国药学杂志

OBJECTIVE: To review and analyze the specificity and dynamic changes in developing the Risk Evaluation and Mitigation Strategy (REMS) in oncology products. METHODS: Based on FDA's requirement for REMS for some high-risk drugs and biologics, the REMS literatures of oncology products were tracked and accessed. The approved and released REMS programs of anti-cancer drugs were summarized and analyzed. RESULTS: REMS is a key tool for FDA to help manage and ensure the safe use of the medications. Though a disproportionate number of drugs with complex REMS are required in patients with cancer, the percentage of the oncology drugs with REMS requirement is not much higher than non-oncology products. This mainly resulted from the specificity of cancer and chemotherapy, in which much collaborative interaction among health care practitioners as well as the emerging target therapy with highly specificity and selectivity may contribute to minimize risk from medications.CONCLUSION: The necessity of developing REMS for an oncology product depends on its properties and the new circumstances in oncology practice.

Toxicological Study on the Anticancer Bioactive Fraction AMH-T of Lichen / 昆明医科大学学报

Objective To provide safety reference for the development of anti-cancer drugs by evaluating thetoxicological safety of the anticancer bioactive fraction AMH-T of lichen through the understanding of its poisonous nature and the intensity.Methods Acute toxicity test,bone marrow micronucleus test in mice,sperm malformation test in rats,Ames test and short-term repeat drug test in mice were conducted.Results Male mice were injected LD50 of 147 mg/kg and female mice 171 mg/kg.Conclusion Injection of AMH-T has acute toxicity and liver toxicity,but has no genetic toxicity.

Novel inhibitor of DNA ligase IV with a promising cancer therapeutic potential.

Cancer is a dreaded disease where effective and cheap drugs are wanting. A large body of research is trying to identify anti-cancer molecules from nature, including plants, marine organisms, microorganisms, etc., and to ultimately synthesize promising molecules in the laboratory. Antibodies to tumour antigens/ receptors, microtubule inhibitors and DNA linking agents have been developed and used as drugs. Today the thrust is on identifying druggable molecules within the tumour cell. Small molecule inhibitors, targeted against crucial enzymes such as kinases, has led to the discovery of important anti-cancer drugs such as Glivec and Gefitinib. There is a great deal of interest in the development and use of therapeutics that target DNA repair pathways. Raghavan and his group chose Ligase IV as their target in the DNA repair pathway (Srivastava et al. 2012) Maintenance of genomic integrity is essential for cell homeostasis. Efficient repair of DNA damage ensures genomic stability. However, cancer therapies such as radiation and chemotherapy function by damaging genomic DNA, by specifically targeting rapidly dividing cancer cells, ultimately leading to cell death. Most of the cancer cells are repair-deficient, thereby providing a therapeutic opportunity to target DNA repair machinery. Although radiation and genotoxic drugs are initially effective in arresting tumour growth and reducing tumour burden, resistance and disease progression eventually occur. The resistance is acquired due to constant selection pressure by the therapeutics. Genetic mutations in the DNA repair genes are not only the initiating event in a cancer cell but also its limitation because the mutated gene function is often required by the cancer cell to maintain its own survival. This limitation has been exploited to specifically kill the tumour cells by targeting the mutated DNA repair gene while sparing the normal ones, a concept known as ‘synthetic lethality’ (Kaelin 2005). One of the main DNA damage repair pathways is double strand break (DSB) repair, which includes nonhomologous end joining (NHEJ) and homologous recombination (HR). It is plausible that targeting the molecular machinery driving the DNA damage repair (DDR), particularly NHEJ with small molecule inhibitors, will effectively enhance the efficacy of current cancer treatments that generate DNA damage and exploit synthetic lethal interactions. Radiation therapy and chemotherapy leads to DSB where NHEJ plays a major role in providing resistance to these agents in a cancer cell. The initial inhibitor L189 against Ligase I, III and IV reported in literature was non-specific (Chen et al. 2008). Raghavan and his group overcame this limitation by targeted design using specific docking of Ligase IV and comparing with L189 (Srivastava et al. 2012). The clever strategy led to the discovery of a novel specific inhibitor SCR7 for Ligase IV. Using elegant experiments on cell lines and mouse model the authors convincingly demonstrated that SCR7 was a specific Ligase IV inhibitor. SCR7 inhibits end joining of double strand breaks in diverse cell types resulting in tumour regression by activation of p53 mediated apoptosis (figure 1). Notably SCR7 treatment did not result in any adverse effects in mice and did not inhibit Ligase III. The authors have envisaged and addressed the likely limitations of SCR7 as a potential anti-cancer drug in humans and have proposed that cancer cells, due to their higher replication, high DNA damage rate and defective cell-cycle checkpoints, will be more sensitive to SCR7 compared to surrounding normal tissues (Srivastava et al. 2012). This may also reduce the possibility of resistance to SCR7. The therapeutic efficacy of SCR7 could be enhanced by specific delivery of SCR7 to the tumour tissue and as adjuvant cancer therapy.