Oxazoline chemistry. Part 12: A metal-mediated synthesis of DMU-212; X-ray diffraction studies of an important anti-cancer agent

An improved synthesis of the anti-cancer agent DMU-212 (trans-3,4,5,4′-tetramethoxystilbene) is described. The methodology involves the use of a Pd-oxazoline catalyst as a mediator of a regio-selective (Heck) C-C bond formation reaction. A simple isolation step is then used to obtain the title material. The compound has been further characterised in the solid-state by X-ray diffraction methods.     

Chemotherapy control by breath profile with application of SPME‐GC/MS method

Chemotherapy used as a treatment against lung cancer has influence on metabolic processes occurring in healthy cells. The changes of biochemical pathways proceeded inside cells might be observed in expired air. In the experiment, breath analysis was carried out before and after anticancer therapy. Expired air samples were collected from 22 patients with a biopsy confirmed lung cancer. Volatile organic compounds present in breath were analyzed by gas chromatography/mass spectrometry. For enrichment of analytes solid‐phase microextraction technique was applied. Eight fibers covered by different sorbents were tested. Carboxen‐polydimethylsiloxane fiber revealed the highest extraction efficiency in relation to analytes in breath. The data showed that cytostatic drugs increase the concentration of acetone and isoprene in the breath collected after chemotherapy. Volatile metabolites of administrated drugs were not identified in expired air.     

LHRH/TAT dual peptides-conjugated polymeric vesicles for PTT enhanced chemotherapy to overcome hepatocellular carcinoma

Combination therapy such as photothermal therapy (PTT) enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Herein, we developed redox-responsive polymeric vesicles based on the amphiphilic triblock copolymer PCL-ss-PEG-ss-PCL. To avoid the limited therapeutic effect of chemotherapeutic drugs caused by systemic exposures and drug resistance, the redox-sensitive polymeric vesicles were cargoed with two chemotherapeutics: doxorubicin (DOX) and paclitaxel (PTX). Besides, indocyanine green (ICG) was encapsulated, and cell-penetrating peptides and LHRH targeting molecule were modified on the surface of polymeric vesicles. The results indicated that the polymeric vesicles can load different kinds of drugs with high drug loading content, trigger drug release in responsive to the reductive environment, realize high cellular uptake via dual peptides and laser irradiation, and achieve higher cytotoxicity via chemo-photothermal combination therapy. Hence, the redox-responsive LHRH/TAT dual peptides-conjugated PTX/DOX/ICG co-loaded polymeric micelles exhibited great potential in tumor-targeting and chemo-photothermal therapy.     

低渗温热腹腔灌注化疗治疗恶性腹腔积液的临床研究

目的 评价低渗温热腹腔灌注化疗治疗恶性腹腔积液的疗效及不良反应。方法 行腹腔穿刺置单腔中心静脉导管,外接引流袋,记录腹水引流量,当日排放腹水1 500ml 后,予加热至43~45℃注射用双蒸馏水1 000ml 行腹腔灌注,次日重复放液1 500ml,再予加热至43~45℃注射用双蒸馏水1 000ml 行腹腔灌注,并于灌注后腹腔注入顺铂60mg、氟尿嘧啶500mg 并封管,治疗期间常规给予简单水化、对症止吐等治疗。结果 31 例恶性腹腔积液患者共完成低渗温热腹腔灌注化疗42 周期,完全缓解7例,部分缓解15,稳定5 例,进展4 例,完全缓解+ 部分缓解占70.97%。中位进展时间（TTP）3.6个月（2～9 个月）, 中位生存期（MST）5.6 个月。毒副反应以消化道反应为主。结论 低渗温热腹腔灌注化疗治疗恶性腹腔积,在延长患者的生存期、提高生活质量方面效果较好,临床上可推荐应用。     

Application of Non‐Stop‐Flow Differential Pulse Voltammetry at a Tubular Detector of Silver Solid Amalgam for Electrochemical Determination of Lomustine (CCNU)

An application of the flow differential pulse voltammetry with tubular detector based on silver solid amalgam for determination of antineoplastic drug lomustine in pharmaceutical preparations is presented. The highest sensitivity was obtained in [0.10 mol dm^?3 MES; 2.00 mol dm^?3 NaCl; pH 6.0]:EtOH (9 : 1) with flow rate 0.50 mL min^?1, and the magnitude of the modulation amplitude ?0.070 V. The calibration dependence was linear in the range 1×10^?6–1 × 10^?4 mol dm^?3 (R²=0.999). The limit of detection was 1.5×10^?7 mol dm^?3. This method was successfully used for determination of lomustine in real samples of chemotherapy drug CeeNU Lomustine 40 mg.     

LHRH/TAT dual peptides-conjugated polymeric vesicles for PTT enhanced chemotherapy to overcome hepatocellular carcinoma

Combination therapy such as photothermal therapy (PTT) enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Herein, we developed redox-responsive polymeric vesicles based on the amphiphilic triblock copolymer PCL-ss-PEG-ss-PCL. To avoid the limited therapeutic effect of chemotherapeutic drugs caused by systemic exposures and drug resistance, the redox-sensitive polymeric vesicles were cargoed with two chemotherapeutics: doxorubicin (DOX) and paclitaxel (PTX). Besides, indocyanine green (ICG) was encapsulated, and cell-penetrating peptides and LHRH targeting molecule were modified on the surface of polymeric vesicles. The results indicated that the polymeric vesicles can load different kinds of drugs with high drug loading content, trigger drug release in responsive to the reductive environment, realize high cellular uptake via dual peptides and laser irradiation, and achieve higher cytotoxicity via chemo-photothermal combination therapy. Hence, the redox-responsive LHRH/TAT dual peptides-conjugated PTX/DOX/ICG co-loaded polymeric micelles exhibited great potential in tumor-targeting and chemo-photothermal therapy.     

HnRNP K and PDI marked response to chemotherapy to human colorectal cancer cells

5‐Fluorouracil has been the chemotherapy agent of first‐choice for colorectal cancer for many years, but since there are no proven predictors of a patient's response to therapy, all patients receive similar treatment. Consequently, identification of biomarkers for therapeutic effect is crucial for the development of novel therapeutic strategies. Two human colorectal cancer cell lines of different metastatic potential (LoVo and SW480) were studied. IC50 of 5‐FU for both cell lines were measured by 3‐(4,5‐dimethy‐lthiazol‐2‐yl)‐2,5‐diphenyltetrazolium assay and validated by cell cycle analysis. Then the cell lines were treated with 5‐FU at IC50 concentration and protein was extracted for 2‐DE. Differential protein spots were examined by MALDI‐TOF/TOF MS. The expression levels of the different proteins were further confirmed by Western blot and immunofluorescence analyses. Eleven proteins were identified. Expression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in LoVo cells was higher than in SW480 cells, while protein disulfide isomerase (PDI) displayed the opposite trend. After treatment with 5‐FU, the expression of hnRNP K in LoVo decreased more significantly than in SW480, while PDI in SW480 increased more significantly than in LoVo cells. Conclusion: hnRNP K and PDI in the two cell lines have different expression characteristics. The sensitivity to 5‐FU is not consistent in tumor progression. It may assist in development of novel treatment strategies for colorectal cancer metastasis.     

Immunogenic Cell Death Inducing Metal Complexes for Cancer Therapy

Cancer is one of the deadliest diseases worldwide. Recent statistics have shown that metastases and tumor relapse are the leading causes of cancer-associated deaths. While traditional treatments are able to efficiently remove the primary tumor, secondary tumors remain poorly accessible. Capitalizing on this there is an urgent need for novel treatment modalities. Among the most promising approaches, increasing research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Preliminary studies have shown that immunogenic cell death inducing compounds could be able to overcome metastatic and relapsing tumors. Herein, the application of metal complexes as immunogenic cell death inducing compounds is systematically reviewed.     

Observation of reversible,rapid changes in drug susceptibility of hypoxic tumor cells in a microfluidic device

Hypoxia is a major stimulus for increased drug resistance and for survival of tumor cells. Work from our group and others has shown that hypoxia increases resistance to anti-cancer compounds, radiation, and other damage-pathway cytotoxic agents. In this work we utilize a microfluidic culture system capable of rapid switching of local oxygen concentrations to determine changes in drug resistance in prostate cancer cells. We observed rapid adaptation to hypoxia, with drug resistance to 2 μM staurosporine established within 30 min of hypoxia. Annexin-V/Sytox Green apoptosis assays over 9 h showed 78.0% viability, compared to 84.5% viability in control cells (normoxic cells with no staurosporine). Normoxic cells exposed to the same staurosporine concentration had a viability of 48.6% after 9 h. Hypoxia adaptation was rapid and reversible, with Hypoxic cells treated with 20% oxygen for 30 min responding to staurosporine with 51.6% viability after drug treatment for 9 h. Induction of apoptosis through the receptor-mediated pathway, which bypasses anti-apoptosis mechanisms induced by hypoxia, resulted in 39.4 ± 7% cell viability. The rapid reversibility indicates co-treatment of oxygen with anti-cancer compounds may be a potential therapeutic target.