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Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand

Acta Pharmacologica Sinica 2005年第11期26卷 1373-1381页

作者： Fang FANG~2, Ai-ping WANG~2, Shi-fang YANG~3 ~2 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, beijing 100050 ~3 beijing sunbio biotech ltd, beijing 100081, china Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China beijing sunbio biotech ltd Beijing China

Aim: To investigate the antitumor activity and safety of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmh TRAIL). Methods: Antitumor activity of rmh TRAIL was evaluated by using several tumor cell lines by MTT assay in vitro, and by using a mouse xenograft model in vivo, rmh TRAIL-induced apoptosis in tumor cells was detected by cell death enzyme-linked immunosorbent assay (ELISA), TdT-mediated dUTP nick-end labeling (TUNEL) assay and flow cytometry. The safety of rmh TRAIL was also evaluated in several normal human cell lines. Results: At the concentration of 0.32-1 000 ng/mL, rmh TRAIL remarkably inhibited the proliferation of 5 tumor cell lines from lung, colon, and breast cancer compared with wild type (wt TRAIL) in vitro, whereas at the concentration of 1 ng/mL-10 μg/mL, rmh TRAIL showed no or mild cytotoxicity in the normal cell lines, rmh TRAIL (3,15 mg/kg, ip, once daily for 10 d) exerted a significant inhibition on the growth of xenograft tumor NCI-H460 in nude mice compared with the saline group (P<0.01), and was more potent than wt TRAIL, a positive control. The apoptosis of NCI-H460 cells was markedly induced in a concentration-dependent and time-dependent manner after rmh TRAIL treatment. The percentage of apoptotic cells induced by rmh TRAIL in NCI-H460 cells was significantly higher than that by wt TRAIL. Conclusion: rmh TRAIL provided potent antitumor activity in vivo and in vitro, whereas most normal human cells were resisitant to rmh TRAIL. The results suggested that rmh TRAIL might be a useful anticancer agent in future.

关键词： antineoplastic agents tumor necrosis factorrelated apoptosis-inducing ligand apoptosis flow cytometry NCI-H460 cells

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