Comparison of the effects of recombinant human endostatin and docetaxel on human umbilical vein endothelial cells in different growth states / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Recombinant human endostatin (rh-endostatin, Endostar) has been proved to be an inhibitor of angiogenesis. Docetaxel has been also considered as a common chemotherapeutic agent with inhibition of angiogenesis of malignancies. However, their function has been seldom compared and a best synergism protocol is not determined. This study aimed to compare the effects of two drugs, investigate their combined impact on human umbilical vein endothelial cells (HUVECs), a molecular basis and find ideal protocols to inhibit endothelial cell proliferation.</p><p><b>METHODS</b>HUVECs on confluent growth or activated by vascular endothelial growth factor (VEGF) were treated by rh-endostatin or/and docetaxel at respective gradient concentration in following operations as cell proliferation determined by MTT assay, cell cycle distribution, apoptosis and markers of CD146, CD62E and CD105 detected by flow cytometery, the structure of the channel formed by HUVECs measured by tube formation count.</p><p><b>RESULTS</b>Rh-endostatin exhibited time dependent inhibition of proliferation while docetaxel showed both time and dose dependent inhibition. HUVECs accumulated in G(0)-G(1) with decreased numbers of cells in G(2) after a single treatment of rh-endostatin or that followed by docetaxel treatment. Cells accumulated in G(2) after both a single docetaxel and simultaneous administration. Both the number of cells in G(0)-G(1) and apoptotic cells were increased by docetaxel followed by rh-endostatin treatment. The number of non-apoptotic cells at G(0)-G(1) was increased by first administering rh-endostatin then docetaxel. Sequential treatment of docetaxel followed by rh-endostatin resulted in the greatest increase in apoptosis (34.7%) and the second highest apoptosis was seen with simultaneous administration (18.2%). Expression of CD146 and CD105 on confluent HUVECs was reduced at certain doses of rh-endostatin and/or docetaxel. However, rh-endostatin reduced CD105 without any apparent impact on either CD146 or CD62E expression, whereas these markers were down-regulated by docetaxel after pre-activation by VEGF. Rh-endostatin treatment maintained tube-like structures for a limited time. In contrast, docetaxel swiftly reduced tube formation. Simultaneous treatment, or docetaxel followed by rh-endostatin, exhibited a stronger inhibition on tube formation than either agent alone.</p><p><b>CONCLUSIONS</b>Both rh-endostatin and docetaxel can inhibit HUVEC proliferation while the high apoptotic rate after combined administration was probably owing to different sequent administration by docetaxel followed by rh-endostatin or simultaneous treatment. Both proliferation and adhesion molecules on HUVECs of confluent growth are down-regulated by the two drugs. The rh-endostatin decreased proliferation markers, but only slightly modified adhesion molecules, while both markers were down-regulated by docetaxel on HUVECs activated by VEGF. Rh-endostatin could maintain adhesion of HUVECs at first then induce cells apoptosis to damage tube formation. We hypothesize that it could lead to vascular normalization in short time. In contrast, docetaxel can suppress HUVEC proliferation, adhesion, and reduced tube formation swiftly due to its cytotoxicity. Combined treatments can induce a synergistic inhibition of tube formation.</p>

Analysis of cavitation of advanced NSCLC treated by rh-endostatin combined with NP chemotherapy / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the significance of intra-tumoral cavitation in the patients with advanced NSCLC treated by rh-endostatin plus NP chemotherapy.</p><p><b>METHODS</b>Fifty-seven patients with advanced NSCLC were randomly assigned to receive chemotherapy with rh-endostatin plus NP or NP alone. The numbers of activated circulating endothelial cells (aCECs) were measured by flow cytometry. Chest computed tomography was performed to evaluate the efficacy after 2 cycles of chemotherapy.</p><p><b>RESULTS</b>Cavitation occurred in 5 of 29 patients in the rh-endostatin plus NP group, but not in any case of the NP group. Of the 5 patients, there were 2 males and 3 females, with pathological types of 3 adenocarcinomas, 1 adenosquamous cell carcinoma and 1 sarcomatoid carcinoma. All of these 5 cases had a peripherally located tumor in the CT scan. There was only one cavity in each case and most of these were roundish. Four cavities were situated in the center of the tumor and another one was eccentric. There were 3 cavities with thin wall and 2 with thick wall. Their average diameter was 2.7 cm. No hemoptysis occurred in these 5 patients. The blood-supply of the tumors showed by perfusion CT images was inhibited in 3 cases after treatment. The average number of aCECs decreased from 323.2/10(5) to 33.0/10(5) after treatment.</p><p><b>CONCLUSION</b>Intratumoral cavitation is a peculiar imaging characteristics after anti-angiogenic therapy, which may be caused by inhibition of blood-supply to the tumor. CT perfusion imaging and measurement of activated circulating endothelial cells may be helpful to predict the efficacy of anti-angiogenic therapy combined with chemotherapy.</p>