Using a zebrafish xenograft tumor model to compare the efficacy and safety of VEGFR-TKIs.

PURPOSE: We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), axitinib, lenvatinib, pazopanib, apatinib, cabozantinib, sunitinib, semaxanib, sorafenib, and regorafenib, in parallel. METHODS: CT26 and GL261 tumor cells were implanted into the perivitelline space of Tg (flk1: eGFP) zebrafish to construct a xenograft tumor model. VEGFR-TKIs' antiangiogenic efficacy was quantified using AngioTool software, and the median effective dose (ED50) was calculated. The toxicity was evaluated by calculating the median lethal dose (LD50) and gross morphological changes. Cardiac toxicity was further assessed by heart rate, heart rhythm, the distance between the sinus venosus (SV) and bulbus arteriosus (BA), and pericardial edema. RESULTS: Using the zebrafish xenograft tumor model, we found that all nine VEGFR-TKIs exhibited antiangiogenic abilities, but the effectiveness of semaxanib was worse than that of other VEGFR-TKIs. Meanwhile, the zebrafish toxicity assay showed that all tested VEGFR-TKIs were associated with cardiac-related toxicity, especially apatinib and axitinib, which caused serious pericardial edema in zebrafish at relatively low concentrations. A narrow therapeutic window was found for most VEGFR-TKIs, and the simultaneous occurrence of toxic effects of semaxanib was recognized. CONCLUSION: Our findings showed the potential of using a zebrafish xenograft tumor model to accelerate VEGFR-TKI screening and further the development of more efficient and less toxic VEGFR-TKIs.

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

Content Determination of Cantharidin in Lytta caraganae by HPLC / 中国药房

OBJECTIVE:To establish the method for content determination of cantharidin in Lytta caraganae,and to use the result as the extract screening evidence of L. caraganae source material. METHODS:Ultrasonic extraction method was used to extract cantharidin from L. caraganae using acetone as solvent. HPLC method was adopted to determine the content of cantharidin. The determination was performed on C18column with mobile phase consisted of methanol-water(23:77)at flow rate of 1.0 mL/min. The detection wavelength was set 230 nm,the column temperature was set at 35 ℃,and sample size was 10 μL. The content of cantharidin in L. caraganae was determined and compared with the results of content determination by the method stated in Chinese Pharmacopeia(using chloroform as extraction solvent). RESULTS:The liner range of cantharidin were 0.2-1.0 mg/mL (r=0.998 8)with average methodology recovery rates of 101.1%(RSD=1.7%,n=6). The average content of cantharidin in L. caraganae was 0.932%(n=3),while the content of cantharidin was 0.793%(n=3)determined by the method stated in Chinese Pharmacopeia. Both were higher than the requirement of Chinese Pharmacopeia that the content of cantharidin in scource material of cantharidin was higher than 0.35%. CONCLUSIONS:Established method is accurate and reliable for the content determination cantharidin in L. caraganae. The content of cantharidin is up to the standard of Chinese Pharmacopeia,and can be used as source material for exacting cantharidin.

Gas Chromatographic Fingerprint of Oleic Acid of Whitmania pigra Whitman / 广州中医药大学学报

Objective To establish the gas chromatographic(GC) fingerprint of oleic acid of Whitmania pigra Whitman for its quality control. Methods Ten batches of Whitmania pigra from different sources and processed by different methods were analyzed with Agilent 6890N gas chromatography detector on DB-WAX(30 mm × 0.32 mm × 0.25μm)column at the vaporizing temperature of 270℃, column temperature of 130℃and flame ionization detector (FID) temperature of 280℃. We used a software of Similarity Evaluation System for Chromatographic Fingerprint of TCM(Version of 2004A) published by Chinese Pharmacopoeia Commission to calculate GC similarity. Results Oleic acid content of Whitmania pigra processed by different methods had significant differences (F2,7 = 7.350, P = 0.019). The oleic acid content of samples dried after washing with clean water significantly differed from that of the samples processed by alumen or the slices dried naturally(P = 0.021, P= 0.009). The similarity of the fingerprints was in the range of 0.458 - 0.998. The similarity of samples from Lipu of Guangxi Province was the lowest. Conclusion The fingerprints of most of the samples have very high similarity. The established GC fingerprints can be used to effectively identify the qualified or inferior Whitmania pigra products, which will provide some reference for the quality control of Whitmania pigra.