RESUMEN
Aims Toevaluatethepharmacodynamic efficacy of different types of antiangiogenic agents as HM-3 on a non-small cell lung cancer xenografts tumor model .To explore the interaction between the antian-giogenic agents and the tumor microenvironment,and to offer suggestions for clinical therapy.Methods Thenon-smallcelllungcarcinomaxenograftmodelwas established in Balb/c nude mice.The model mice were treated with Docetaxel(10 mg·kg-1 )as the positive control.The mice were parallelly treated with,HM-3 at the doses of 3 mg · kg-1 and 48 mg · kg-1 and, Avastin(5 mg·kg-1 ).The parameters include tumor volume,tumor weight and immunohistochemical analy-sis.Result Animalexperimentsshowedthatdocetaxel had good anti-tumor activity.Tumor growth inhibition by tumor weight of G2 docetaxel(10 mg·kg-1 )group was 60. 80%.Tumor growth inhibition by tumor weight of G3 HM-3(3 mg·kg-1 )group,G4 HM-3(48 mg· kg-1 )group ,G4 Avastin(5 mg·kg-1 )group,were 43. 60%,-34. 80%,44. 40%,respectively.Con-clusion Theantigiogeniceffectisaffectedbytumor growth stage,tumor microenvironment and their work-ing mechanisms.Angiogenesis inhibitors HM-3 has a certain effect of inhibiting tumor growth,but to little a-vail.HM-3 shows on inhibitory effect in a dose-de-pendent manner at the doses of 0~6 mg·kg-1 .HM-3 at a high dose of 48 mg · kg-1 has no inhibitory but promoting effects on human non-small cell lung carci-noma A549 xenografts in nude mice .Special dose-effect relationship indicates that dosage should be paid attention to in the clinical use of blood vessel inhibi-tors.
RESUMEN
PEGylation improves the pharmacokinetic and pharmacodynamic properties of polypeptide drugs. After PEGylation, the modified HM-3 (PEG-HM-3) exhibited a prolonged half-life in blood. In this paper, we evaluated the anti-rheumatic effect of PEG-HM-3, and investigated the target for angiogenesis and inflammation. The anti-rheumatic activity of PEG-HM-3 was documented in an adjuvant-induced arthritis (AIA) model. PEG-HM-3 significantly decreased the paw increase percentage and clinical scores, inhibited characteristic signs such as synovial hyperplasia, pannus formation, inflammatory infiltration and bone erosion in histological analysis, and reduced bone erosion with the X-ray analysis of the hint paws of rats. The target for angiogenesis and inflammation was assessed with in vivo and in vitro techniques. The in vivo experiments confirmed that PEG-HM-3 decreased the number of blood vessels in rheumatic synovium, reduced the level of serum anti-CII autoantibodies, and decreased the levels of synovial TNF-alpha and VEGF in a collagen-induced arthritis (CIA) model. The in vitro results confirmed that the anti-angiogenic effect of PEG-HM-3 was mainly achieved through the inhibition of HUVEC migration. PEG-HM-3 inhibited the mitotic effects in the T-cell population. PEG-HM-3 could significantly inhibit the TNF-alpha and VEGF levels in the LPS-stimulated macrophage and the latter effect was stronger than that seen with HM-3. Furthermore, the simulated molecule docking result showed that the RGD motif of PEG-HM-3 inserted into the pocket site of integrin αvß3, and PEG-HM-3 had a higher predicted affinity with integrin αvß3 compared to the predicted affinity of HM-3 and integrin αvß3. This study has uncovered that PEGylate HM-3 could present an anti-rheumatic bioactivity with a less frequent schedule, and PEG-HM-3 exhibited its anti-rheumatic effects by inhibiting angiogenesis and inflammation. Furthermore, the main targeting site has been confirmed, which explained the changes in the bioactivity of PEG-HM-3.
