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The recombinant sTRAIL has been in clinical trial for various human malignancies. However, the half-life time of sTRAIL is very short, which might be an important factor influencing its clinical efficacy for cancer therapy. We previously reported the recombinant adeno-associated virus (AAV)-encoding sTRAIL95-281-mediated sTRAIL expression in vivo up to 8 months and suppressed tumor growth markedly in mouse xenografts. In the present study, we further evaluated the clinical potency for cancer gene therapy and the safety in mouse and non-human primates. The mouse models with HCT-116, NCI-H460 and BEL-7402 cancers were injected intraperitoneally with a single dose of 1.0 × 1011, 1.0 × 1010 and 1.0 × 109 vg of rAAV2-sTRAIL95-281 virus, respectively. The cynomolgus monkeys were injected (i.m.) with a single dose of rAAV2-sTRAIL95-281 of 1 × 1011, 3 × 1011 and 1 × 1012 vg, corresponding to 6-, 20- and 60-fold of intended use dosage for humans, respectively. The efficacy, pharmacology and toxicity of rAAV-sTRAIL in the animals were analyzed accordingly. The tumor inhibitory rates reached 44-76%, 48-52% and 55-74% in the three tumor models, respectively, and they had no influence on mouse spontaneous activity. Administration (s.c.) of a single dose of rAAV2-sTRAIL95-281 virus of 1.0 × 109 or 1.0 × 1010 vg in mice with implanted tumor led to mainly distribution in the spleen, liver, implanted tumor, blood, injected site of muscle and bone marrow. Two weeks later, there was no rAAV2-sTRAIL95-281 detected in blood and bone marrow, and it significantly decreased in other tissues and organs and then gradually cleared away in 4-12 weeks after administration. There was no rAAV2-sTRAIL accumulation in the animal's body and no influence on the body weights. Administration (i.v.) did not cause animal death, and no dose-related abnormal clinical symptoms were found in the mice. There were no abnormal tissue and organ found in all animals. Long-term toxicity test in cynomolgus monkeys did not cause rAAV2-sTRAIL95-281-related toxic and side effects, except that anti-AAV and anti-sTRAIL antibodies were generated. In conclusion, these data demonstrated that administration of rAAV2-sTRAIL95-281 in mice and in cynomolgus monkeys is safe without obvious toxic and side effects to the animals, and throw light on pharmacokinetics and safety in human clinical trials for cancer gene therapy.