| ObjectiveThe purpose of this work was to analyze the efficacy of cryotherapy or cryotherapy combined with immunological treatment in tumor-bearing mice. To provide an experimental and theoretical basis for the treatment of clinical patients with double primary tumors, more than the original tumors, and metastatic tumors.The therapeutic effect was assessed by the serum cytokines (TNF-α, IFN-γ) content, survival time and tumor weight of mice which were rechallenged with tumor cells.MethodsKunming mice were inoculated subcutaneous with S180 sarcoma cells, and were randomly divided into four groups. For the treatment of tumors were cryotherapy (group A), immunotherapy (group B), cryo-immunotherapy (group C) and saline control group (group D). On the 10 day after the end of treatment, each group was divided to two groups. Four groups of mice were rechallenged with H22 hepatoma cells, and other were rechallenged with S180 sarcoma cells. The therapeutic effect was assessed by survival time, tumor weight, serum cytokines (TNF-α,IFN-γ) content. Results1 After the treatment of cryotherapy or immunotherapy, one mouse was regressed in the cryotherapy group which was initial inoculated S180 sarcoma cells (1/40). Also, one case were cured in cryo-immunotherapy group (1/40) .2 The survival time of mice after rechallenged with tumor cells.2.1 The survival time(days) of mice after rechallenged with S180 sarcoma cells.The average surviving time of mice in group A was 91.3±6.83, group B was 92.5±10.51, group C was 114.4±9.08, and group D was 59.7±9.17. Group A, B, and C, the average surviving time of mice were longer than Group D, and showed statistically significant difference(all P<0.01). The average surviving time of group B longer than group A , but no significant difference between groups (P>0.05). The average surviving time of group C longer than group A and B, and showed statistically significant difference between groups (both P<0.01). The results show : cryotherapy, immunotherapy, cryo-immunotherapy is effective in enhancing the ability for anti-homologous tumor cells attacked again, prolonging the surviving time of tumor-bearing mice, and cryo-immunotherapy has a better therapeutic effect than others.2.2 The survival time(days) of mice after rechallenged with H22 hepatoma cells.The average surviving time of mice in group A was 44.6±4.45, Group B was 55.5±3.98, Group C was 72.1±5.74, and Group D was 42.3±6.67. Group B and Group C, the average surviving time of mice were longer than Group D, and showed statistically significant difference(both P<0.01); Group A, the average surviving time of mice was longer than Group D, but no significant difference between groups(P>0.05). The average surviving time of group B longer than group A , a statistically significant difference between groups (P<0.01). The average surviving time of group C longer than group A and B, and showed statistically significant difference(both P<0.01). The results show : cryotherapy, immunotherapy, cryo-immunotherapy is effective in enhancing the ability for anti-heterogeneous tumor cells attacked again, prolonging the surviving time of tumor- bearing mice, and cryo-immunotherapy has a better therapeutic effect than any other simply treatment.3 The tumor weight in mice which were rechallenged with tumor cells.3.1 The tumor weight(g) in mice which were rechallenged with S180 sarcoma cells.After rechallenged with S180 sarcoma cells, tumors occurred in group A, B, and D, but two cases mice no tumor growth in group C. The average tumor weight in group A was 0.541±0.0696, and compared with group D that the inhibition ratio was 51.44%. In group B was 0.507±0.0801, and inhibition ratio was 54.49%. In Group C was 0.164±0.1071, and the inhibition ratio was 85.29%. In group D was 1.114±0.1524. Group A, B, and C , the average tumor weight lighter than in Group D, and showed statistically significant difference(all P<0.01). In group B, the average tumor weight lighter than group A, however, no significant difference between two groups (P >0.05). In group C, the average tumor weight lighter than group A and B, and showed statistically significant difference(both P<0.01). The results show: cryotherapy, immunotherapy, cryo-immunotherapy can inhibit the same tumors growth on the tumor-bearing mice which are rechallenged by the homologous tumor cells. and cryo-immunotherapy has a better therapeutic effect than any other simply treatment.3.2 the tumor weight(g) in mice which were rechallenged with H22 hepatoma cells.After rechallenged with H22 hepatoma cells, tumors occurred in all the mice. The average tumor weight in group A was 1.331±0.1264, and compared with group D that the inhibition ratio was 7.51%. In group B was 1.436±0.1639, the inhibition ratio was 0.21%. In group C was 0.921±0.1007, and the inhibition ratio was 36.00%. In Group D was 1.439±0.2045. The average tumor weight lighter in Group C than in group D, a significant difference between groups (P <0.01). In group A and group B, the average tumor weight lighter than group D, but no significant differences between the groups (both P>0.05). The average tumor weight lighter of group A than the group B, but no significant differences between the two groups (P> 0.05). The average tumor weight of group C lighter than in group A and B, and showed statistically significant difference(both P<0.01). The results show: cryo-immunotherapy can inhibit the tumor growth on the mice which are rechallenged with heterogeneous tumor cells. After simple cryotherapy or immunotherapy , there are no significant inhibition of tumor growth on the mice which are rechallenged with heterogeneous tumor cells.4 The serum levels of IFN-γin mice which were rechallenged with tumor cells.4.1 The serum levels of IFN-γ(pg/ml) in mice which were rechallenged with S180 sarcoma cells.The average serum level of INF-γin group A was 11.231±1.466. In group B was 12.042±2.420. In group C was 18.163±3.347. In group D was 4.871±2.279. The average serum levels of IFN-γin group A, B, and C higher than group D, and showed statistically significant difference(all P<0.01). The average serum level of IFN-γin group B higher than group A, however, no significant difference between groups (P>0.05). The average serum level of IFN-γin group C higher than group A and B, showed statistically significant difference(both P<0.01). The results show: after treated by cryotherapy, immunotherapy, cryo-immunotherapy, the serum INF-γlevels in mice which rechallenged with the same tumor cells higher than the control group, the average serum INF-γlevel of group C which is treated by cryo-immunotherapy is more effective.4.2 The serum levels of IFN-γ(pg/ml) in mice which were rechallenged with H22 hepatoma cells.The average serum level of INF-γin group A was 9.171±1.443. In group B was 9.448±1.639. In group C was 13.096±1.618. In group D was 4.506±1.968. In group A, B, and C, the average levels of serum IFN-γhigher than Group D, significant difference between the groups (all P <0.01). In group B, the average level of serum IFN-γhigher than group A, however, no significant difference between groups (P >0.05). In group C ,the average level of serum IFN-γhigher than group A and B, there were a significant difference between groups (both P <0.01). The results show: after treated by cryotherapy, immuno-therapy, cryo-immunotherapy, the serum INF-γlevels in mice which rechallenged with the heterogeneous tumor cells higher than the control group, the average serum INF-γlevel in group C which is treated by cryo-immunotherapy is more effective.5 The serum TNF-αlevels in mice which were rechallenged with tumor cells.5.1 The serum levels of TNF-α(pg/ml) in mice which were rechallenged with S180 sarcoma cells.The average level of serum TNF-αin group A was 6.674±0.958, in group B was 8.118±0.835, in group C was 10.043±0.762, in group D was 4.661±0.463. Group A, B, and C higher than the average level of serum TNF-αin group D, significant difference between the groups (all P<0.01). In group B , the average level of serum TNF-αhigher than group A, there was a significant difference between groups (P<0.01). In group C, the average level of serum TNF-αhigher than in group A and B, there were a significant difference between groups (both P <0.01). The results show: after treated by cryotherapy, immunotherapy, cryo- immunotherapy, the serum TNF-αlevels in mice which rechallenged with the same tumor cells higher than the control group, the average serum TNF-αlevel of group C which is treated by cryo-immunotherapy is more effective.5.2 The serum levels of TNF-α(pg/ml) in mice which were rechallenged with H22 hepatoma cells.The average level of serum TNF-αin group A was 8.810±0.673, in group B was 9.231±0.861, in group C was 11.789±1.079, in group D was 5.196±1.855. Group A, B and C higher than the average level of serum TNF-αin group D, significant difference between the groups (all P<0.01). In group B, the average level of serum TNF-αhigher than in group A, however, no significant difference between groups (P>0.05). In group C ,the average level of serum TNF-αhigher than the group A and group B, there were a significant difference between groups (both P<0.01). The results show: after treated by cryotherapy, immunotherapy, cryo-immunotherapy, the serum TNF-αlevels in mice which rechallenged with the heterogeneous tumor cells higher than the control group, the average serum TNF-αlevel of group C which is treated by cryo-immunotherapy is more effective.Conclusion1 We can cure a few of tumor-bearing mice which are inoculated with S180 sarcoma cells by cryotherapy and prolong the surviving time of mice.2 Cryotherapy can enhance anti-tumor immunity of tumor- bearing mice, which will effectivly inhibit the homologous tumor growth that is rechallenged, and prolong the surviving time of mice. Also, it partly inhibites heterogeneous tumor growth which is rechallenged, and prolongs the surviving time of tumor-bearing mice.3 Intraperitoneal injection of IL-2 can enhance the anti- tumor ability for tumor-bearing mice, effectivly inhibit the homologous tumor growth which is rechallenged, and extend the surviving time of mice. Also, it partly inhibites heterogeneous tumor growth which is rechallenged, and prolongs the surviving time of tumor-bearing mice.4 During the cryotherapy treatment combined with IL-2 could effectively improved the anti-tumor immune respone, stimulated the tumor-bearing mice serum cytokines level which are rechallenged with homologous or heterogeneous tumor cells. The surviving time of mice and the inhibition ratio of tumor significantly better than simple cryotherapy or immunotherapy treatment.5 The study shows that will better activatie the immune system of cancer patients, after signle tumor treated by cryotherapy combined with IL-2. An effective anti-tumor response will inhibit the growth of homologous and heterogeneous tumors. Experimental basis be provided for the treatment of clinical patients with double primary tumors, more than the original tumors, and metastatic tumors.
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