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Acta Pharmacologica Sinica 2005 November; 26 (11): 1373-1381; doi: 10.1111/j.1745-7254.2005.00206.x |
| Original Article | [ Full text ] |
| Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand1 |
Fang FANG2, Ai-ping WANG2, Shi-fang YANG3 2Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050; 3Beijing Sunbio Biotech LTD, Beijing 100081, China |
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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.
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Keywords: antineoplastic agents; tumor necrosis factor-related apoptosis-inducing ligand; apoptosis; flow cytometry; NCI-H460 cells |
| 1 Project supported by the Innovation Fund for Small Technology-based Firms (No 04C26211100286) and High Technology Research and Development Program of China (863 Program) (No 2005AA2Z3H50) |
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