Original Articles

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

Authors: Fang Fang, Ai-ping Wang, Shi-fang Yang

Abstract

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 0.32–1000 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 mug/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.
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