| Background:Etoposide is a podophyllum-like semisynthetic drug which was often used in malignant hematologic system neoplasms and solid tumor. it can form a triplet complex with DNA and topoisomerase Ⅱthat can block the link activity of the enzyme and cause the ALL-1 gene which including MLL,Htrxl and HRX break and rearrangemant in breakpoint cluster region.Furthermore etoposide can cause DNA damage via free radical induced by dehydrognase,which is often considered to be related to therapy-related leukemia.Amifostine is a broad spectrum cytoprotector that can decrease the toxicity of alkylating agents to hematopoietic stem cell,kidney, hemorrhagic cystitis,nervous system,gastrointestinal tract,lung and so on.Whether the amifostine is a protector to the DNA damage and hematopoietic lesion induced by etoposide remains unclear according to research report all over the world.Object :The object of our study was to investigate the DNA damage and hematopoietic lesion of the mice induced by etoposide.and also clarify the effect of pretreatment use of amifostine on the DNA damage and hematopoietic lesion.Methods:The Kunming strain mice were subjected in our study and randomed divided into nine groups(A1,A2,A3,B1,B2,B3,C,D,E).Every group included identical samples.Three differet doses of etoposide were given to group A(A1,A2,A3 vs VP-16 1mg/kg,5mg/kg,15mg/kg).and the same doses of etoposide combined amifostine were given to group B(B1,B2,B3 vs VP-161mg/kg,5mg/kg,15mg/kg).The same volume of saline and same dose of amifostine was given to group C and D. Cyclophosphamide was given alone to group E. The frequency of micronuclei in polychromatic erythrocytes was compared in different groups.Singe cell gel electrophoresis was used to investigate the DNA damage and DNA migration of mice treated with etoposide.The survival rate test,peripheral blood cell count,bone marrow CFU-GM count were studied to investigae the effect of amifostine on hematopoietic system lesion caused by etoposide. Statistics analysis was used to the results of our research to determinate whether the pretreatmen use of amifostine could decrease the toxicity of the etoposide.Results:The frequency of micronuclei in group B1,B1 and B3 was significantly lower than that of group A1,A2 and A3(1.5±0.5‰,12.9±3.5‰,24.0±4.4‰ vs 7.8±2.6‰,23.8±5.6‰,47.3±9.8‰.P<0.0.1 7.8).The rates of lymphocytes with DNA damage in group B1,B1 and B3 was obviously lower than that of group A1,A2 and A3 (14.4±2.0%,24.6±4.4%,31.7±5.2% vs 26.5±5.1%,46.2±8.1%,70.2±7.2%.P<0.0.1).The DNA migration B1,B1 and B3 was obviously smaller than that of group A1,A2 and A3 (6.2±2.7,29.9±5.7,51.1±7.5um vs 35.6±6.1,56.1±8.6,87.9±10.5um.P<0.0.1).The survival rate of 30 days and mean survival days of dead mice in group B1,B1 and B3 were more ameliorated than that in group A1,A2 and A3 (91.7%,83.3%,41.7% vs 75.0%,50.0%,0,9.0,9.5±2.1,8.1±2.6 vs 8.3±1.5,7.5±1.9,6.2±1.8).The peripheral blood WBC count and the bone marrow CFU-GM count of mice at the 1st day ,7th day and 14th day in group B1,B1 and B3 were also significantly ameliorated than that in group A1,A2 and A3 (P<0.01).All the results indicate that the difference between the group A and group B was obviously notable.Conclusion:1. The etoposide can increase The frequency of micronucleatedpolychromatic erythrocytes (MNPCEs),and we found there is a obviously dose-effect relationship between the micronuleus formation and the application of etoposide. WR-2721 was applied prior to etoposide can decrease the MNPCEs.2. Dramatic dose-dependent DNA damage is observed in lymphocyte after application with etoposide.and the damage can reduce by use of amifostine in advance.3. The survival rates of mice will increase when the amifostine was give 30 min prior to the treatment. The mean survival days of dead mice will prolong compare with the pretreament groups. The difference of peripheral blood cell count and CFU-GM count between group A and B was obviously. All these datas indicate amifostin...
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