Study Of Combretastatin A4Phosphate Analogues Antineoplasm In Vitro And In Vivo

It is common for advanced or metastatic solid tumors to be resistant to conventional cytotoxic drugs. Nearly90%of all malignant tumors, of more than200types, are solid tumors, which are critically dependent on a continually developing vascular supply for their growth, progression, and metastasis. Vascular endothelial cells are more genetically stable, homogeneous, and have a lower mutational rate than tumor cells, which makes them a good anti-tumor therapeutic target. Vascular-targeting agents (VTAs) can be divided into two groups:anti-angiogenesis agents and vascular disrupting agents (VDAs).Combretastatin A4was discovered in1989and was originally isolated from a SouthAfrican tree Combretum caffrum. CA4P is a water-soluble prodrug of combretastatin A4.It inhibits tubulin polymerization at the colchicine binding site of β-tubulin leading to cytoskeletal and then morphological changes in immature or proliferating endothelial cells. These changes disrupt tumor blood flow. Endostar, a novel recombinant human endostatin, with an additional nine-amino acid sequence at the N terminus, is more stable than conventional endostatin, which has been demonstrated to inhibit the growth of avariety of human tumors by inhibiting neovascularization Endostar had been shown to inhibit endothelial cell proliferation,migration, and vessel formation. Endostar has a broad spectrum of activity against solid tumors. The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma.In vitro, Endostar could enhance the antineoplasm of CA4P on kinds of tumor cell lines, especially on the human osteosarcoma MNNG/HOS cell line. Endostar had no significant effect in tumor cell cycle, CA4P could lead to G2/M arrest, G2/M disturbance was more obvious when Endostar combinated with CA4P. Realtime PCR shows that Endostar combinated with CA4P could lead to the upregulation of Bax, downregulation of Bcl-2, activation of Caspase3, Caspase8, Caspase9, which then trigger major apoptotic cascades. In vivo, the tumor volumes of the Endostar combined with CA4P group was the smallest, and the standardized uptake value (SUV) of the Endostar combined with CA4P group was lower than that of the other groups by Positron emission tomography imaging (microPET). The Endostar combined with CA4P group had the most poorly perfused center by Dynamic contrast-enhanced ultrasound (DCE-US) or ultrasonic contrast, the highest incisal surface necrosis rate and the lowest microvascular density (MVD) In a word, Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. But CA4P is unstable, needed to administrate repeatly, less active than CA4, How to enhance the antineoplasm effect is the hot spot. The study synthetized a series of CA4P analogue and CA4P micro-capsule, also evaluated the effect of them.The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing anovel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.