Safety Evaluation Of Recombinant Adenovirus Ad-VT

Recombinant adenovirus Ad-VT is a dual specific anti-tumoral recombinantadenovirus, which has both tumor specific restrain and tumor specific replicationabilities. It is also be expected to be a safe, specific and effective tumor clinical drugcandidates, and it is very attractive to develop.Safety, efficacy and quality control are three essential elements of drugs. Thedrug evaluation must be carried out before any new drugs recommended clinicaltrials. Safety evaluation generally includes general toxicity tests (acute toxicity testsand long-term toxicity tests), special toxicity tests, drug dependence test and othertests, such as allergic experiment and so on.In the mice acute toxicity tests of this study, according with the highest titer andthe highest degree of medicine volume of recombinant adenovirus Ad-VT, we set5×1010PFU to be toxicity tests medicine doses. The results show that,5×1010PFU isa safety doses for mice. According to the weight calculation, the dose is about650times as the clinical dose of recombinant adenovirus Ad-VT.In our study, we took three months on the long-term toxicity tests with wistarrats and beagle dogs to evaluate the recombinant adenovirus Ad-VT. The dose oflow-dose group is5×108pfu/kg, which is two times higher than the proposedclinical dose; the middle dose is2.5×109pfu/kg, which is14times higher than theproposed clinical dose; and the high dose is1.25×1010pfu/kg, which is74timeshigher than the proposed clinical dose. We observed and recorded the generalbehavior, weight, body temperature, urine biochemistry, hematology, bloodbiochemistry, antibody levels, pathological histology and ECG of the animals. Inorder to understand the target organ and cumulative toxicity of recombinantadenovirus Ad-VT, determine the range of safe dose. The test results show that, inthe long-term toxicity with wistar rats and beagle dogs, we did not found anyobvious abnormalities with the normal control groups, the indicators fluctuatedwithin the normal range. All of three doses are safe dose.The purpose of safety pharmacological test is to reveal the function of the major physiological systems (such as cardiovascular, respiratory, kidney and centralnervous system). All of these studies could explain the mechanism of action ofspecific organ toxicity. And we should carefully consider the relation between thespecific organ toxicity and human applications or indications. In order to explore thetoxicity of recombinant adenovirus Ad-VT on the animal central nervous system,cardiovascular, digestive system and so on, we study on the general behavior,spontaneous activity, excitability of nervous system, coordination of movement,digestive functions, and digestive system of mouse. The results showed that there isnot any obvious effect on the indicators above after the mice were injected with theproposed clinical dose of recombinant adenovirus Ad-VT.In the systemic allergic test, according to the order of allergic reactions onguinea pigs, we judged the result is0level. The result indicated that recombinantadenovirus Ad-VT will not cause allergic reactions on animals' or people's body. Inthe local irritation test, we evaluated the quadriceps of rabbit based on the evaluationstandard of skin irritation intensity. The results showed that the recombinantadenovirus Ad-VT could irritate the skin slightly without oedema and inflammation.In this research we study on the toxicity of recombinant adenovirus Ad-VTthough acute toxicity tests, long-term toxicity tests, general pharmacology texts andallergy, irritating tests. The results will provide references to clinical tests.