金黄地鼠口腔颊囊癌动物模型在重离子放射治疗中的应用
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摘要
目的：注射法建立金黄地鼠颊囊癌模型,动态观测肿瘤发生进程；探讨碳离子束辐照对机体微量元素以及凋亡相关基因Survivin、Caspase-3表达的影响,为重离子肿瘤治疗和空间辐射危险评估提供实验依据。
材料与方法：1.本研究选取81只健康的金黄地鼠随机分为3组,其中空白对照组(6只),涂抹组(15只),注射组(60只)(又分A, B, C, D, E5个小组)。采用预设浓度为(0.5%,0.4%,0.3%,0.2%,0.1%)的DMBA丙酮注射法和涂抹法(0.5%)作比较建立金黄地鼠颊囊癌模型,采用组织学形态分析两种方法在癌变过程中不同病理阶段的进行大体观察、监测体重并计算肿瘤生长率异同,筛选合适的注射浓度建立口腔鳞癌动物模型。
2.应用碳离子束辐照荷颊囊癌金黄地鼠,观测0、4、6、8、12Gy剂量的重离子束对荷颊囊癌金黄地鼠血中微量元素含量的影响,应用原子吸收光谱仪火焰法测定血清中铁(Fe),铜(Cu),锌(Zn),镁(Mg),钙(Ca)5种微量元素的含量。
3.采用免疫组化SP法检测40例荷金黄地鼠颊囊癌组织中Survivin和Caspase-3的蛋白表达,探讨重离子束辐照对肿瘤组织的影响。
结果：1.注射浓度组0.4%、0.3%、0.2%、0.1%分别在13W,9W,12W,16W时出现约为0.8×0.6cm×0.5cm大小的肿瘤；12W时成癌率分别为25%、87%、42%、58%；而0.5% DMBA丙酮涂抹组,12W时成癌率为48%,死亡率为37%,至18W时颊粘膜才出现高分化鳞癌。
2.金黄地鼠成瘤后,血清中微量Fe、Zn、Cu、Mg元素含量均明显低于正常组(P<0.05)；再经过不同剂量的重离子束辐照后1月,血清中五种微量元素在低剂量时均呈现下降趋势,随之出现升高,到8Gy再呈降低的趋势,存在一定的剂量-反应关系。
3. Survivin在金黄地鼠口腔颊鳞癌组织(OSCC)中阳性表达28例(28/40),在正常口腔粘膜(NOM)中为零表达(0/8)；Caspase-3在金黄地鼠口腔颊鳞癌组织(OSCC)中阳性表达30例(30/40),在正常口腔粘膜(NOM)中为100%(8/8)；经统计学分析,Survivin和Caspase-3在OSCC中的表达有统计学意义(P＜0.05),(12)~C~(6+)离子辐照对OSCC中Survivin的表达有统计学意义(P＜0.05),Caspase-3的表达无统计学意义(P>0.05),辐照与肿瘤临床分期间无统计学意义(P＜0.05)。
结论：1.经筛选采用0.3%DMBA丙酮液注射法可诱发形成口腔鳞癌动物模型,缩短实验周期,降低建模成本。
2.经不同剂量的重离子束局部辐照荷瘤金黄地鼠,会影响血清中微量元素的含量,具有一定临床意义。
3.(12)~C~(6+)离子照射对口腔鳞癌组织中的Survivin和Caspase-3蛋白表达产生影响,下调Survivin的表达,间接调节Caspase-3的活性,参与凋亡调控过程。
Objective:To establish hamsters buckle pouch carcinogenesis model by DMBA injection method, The tumor process changes were observed dynamically. To study the effects of trace elements and the expression of apoptosis related genes Survivin, Caspase-3 in hamster buckle pouch carcinogenesis model after carbon ion beams irradiation, so as to provide experimental evidence for Heavy Ion Clinical Therapy of Oral Cancer and risk assessment for Space Radiation.
Materials and Methods:1.This study selected 81 healthy hamsters, they were randomly divided into 3 groups, including the control group (6), the painted group (15), the injected group (60) (also points A, B, C, D, E 5 Groups).With the DMBA acetone solution injection group, The concentration were used to set up for 0.5%,0.4%,0.3%,0.2%,and 0.1%.but the concentration in the painted group was fit for 0.5%. to induce buckle pouch carcinogenesis model in Syrian Golden Hamsters. For the general observation of the model, the body weight has been monitored and the tumor growth rate calculated. Using histological analysis of the similarities and differences in two methods with different pathological stages of.the carcinogenesis process The concentration of injection method by the screening to establish the appropriate carcinogenesis model of oral squamous cell carcinoma.
2. Exposed with carbon ion beam irradiation of cheek pouch carcinoma in hamster, Observation 0,4,6,8,12 Gy dosage of heavy ion beams on the bearing hamster cheek pouch carcinoma of trace elements of content in blood. Application of flame atomic absorption spectroscopy determinated to flexion-extension (Fe) radiographs, copper (Cu), zinc (Zn) and magnesium (Mg), calcium (Ca) the content of trace elements in serum.
3. Immunohistochemical SP method was detected the expression of Survivin and Caspase-3 protein of cheek pouch carcinogenesis in 40 cases bearing golden hamster and to explore on the impact of tumor tissue in Carbon ion beams irradiation.
Results:1 The injection concentrations (0.4%,0.3%,0.2%,0.1%) of DMBA acetone solution have induced the tumors. Respectively, at 13W,9W,12W,16W, the average size is about 0.8cm× 0.6cm×0.5cm; the carcinogenesis rates at 12W were respectively 25%,87%,42%,58%; but 0.5% DMBA solution with painted group, the carcinogenesis rate was 48%,the death rate was 37%. Well differentiated cheek squamous cell carcinoma was obtained at 18W.
2 In the hamsters borne tumor, the contents of Fe, Zn, Cu and Mg in experimental groups with cheek pouch carcinoma were significantly lower than normal group(P<0.05). After irradiated by 0, 4,6,8,12Gy heavy ion beams, the 4Gy group showed a tendency downward. When the irradiation dose reached 6Gy, the contents of Fe, Zn increased. When it reached 12Gy, the contents decreased.. While Cu, Ca and Mg contents in the group at 8Gy reached to their highest value, and had become lowering until 12Gy. All of the results showed a dose-reaction relationship (P<0.05).
3 The number of the expression of positive Survivin protein were 28 among 40 cases in oral squamous cell carcinoma, the positive rate was 70%, but there was no positive individual in normal oral mucosa (0/8); The Caspase-3 expression were 30 among 40 cases, the positive rate was 75% in oral squamous cell carcinoma, and was 100% in normal oral mucosa (8/8). By statistical analysis, we have found there are differences between oral squamous cell carcinoma and normal oral mucosa. After 12C6+ ion irradiation with different doses,Survivin expression was statistically significant (P<0.05) compared with the OSCC group, but the differences of Caspase-3 expression did not occurred. The 12C6+ ion irradiation group compared with OSCC group was not statistically significant (P>0.05).
Conclusions:1 The 0.3% concentration of DMBA acetone solution is more suitable for the formation of oral squamous cell carcinoma model in Golden Hamster in the short term. This method is benefit to shorten the feeding cycle, reduce costs.
2 Exposed with different doses of heavy ion beam irradiation, there are some changes of content in trace elements of serum, which are of clinical significance.
3 12C6+ ion irradiation can reduce the expression of Survivin, indirectly raise the activity of Caspase-3. It reveals to us the 12C6+ ion irradiation may play a critical role in the regulation of the process of cell apoptosis.
材料与方法：1.本研究选取81只健康的金黄地鼠随机分为3组,其中空白对照组(6只),涂抹组(15只),注射组(60只)(又分A, B, C, D, E5个小组)。采用预设浓度为(0.5%,0.4%,0.3%,0.2%,0.1%)的DMBA丙酮注射法和涂抹法(0.5%)作比较建立金黄地鼠颊囊癌模型,采用组织学形态分析两种方法在癌变过程中不同病理阶段的进行大体观察、监测体重并计算肿瘤生长率异同,筛选合适的注射浓度建立口腔鳞癌动物模型。
2.应用碳离子束辐照荷颊囊癌金黄地鼠,观测0、4、6、8、12Gy剂量的重离子束对荷颊囊癌金黄地鼠血中微量元素含量的影响,应用原子吸收光谱仪火焰法测定血清中铁(Fe),铜(Cu),锌(Zn),镁(Mg),钙(Ca)5种微量元素的含量。
3.采用免疫组化SP法检测40例荷金黄地鼠颊囊癌组织中Survivin和Caspase-3的蛋白表达,探讨重离子束辐照对肿瘤组织的影响。
结果：1.注射浓度组0.4%、0.3%、0.2%、0.1%分别在13W,9W,12W,16W时出现约为0.8×0.6cm×0.5cm大小的肿瘤；12W时成癌率分别为25%、87%、42%、58%；而0.5% DMBA丙酮涂抹组,12W时成癌率为48%,死亡率为37%,至18W时颊粘膜才出现高分化鳞癌。
2.金黄地鼠成瘤后,血清中微量Fe、Zn、Cu、Mg元素含量均明显低于正常组(P<0.05)；再经过不同剂量的重离子束辐照后1月,血清中五种微量元素在低剂量时均呈现下降趋势,随之出现升高,到8Gy再呈降低的趋势,存在一定的剂量-反应关系。
3. Survivin在金黄地鼠口腔颊鳞癌组织(OSCC)中阳性表达28例(28/40),在正常口腔粘膜(NOM)中为零表达(0/8)；Caspase-3在金黄地鼠口腔颊鳞癌组织(OSCC)中阳性表达30例(30/40),在正常口腔粘膜(NOM)中为100%(8/8)；经统计学分析,Survivin和Caspase-3在OSCC中的表达有统计学意义(P＜0.05),(12)~C~(6+)离子辐照对OSCC中Survivin的表达有统计学意义(P＜0.05),Caspase-3的表达无统计学意义(P>0.05),辐照与肿瘤临床分期间无统计学意义(P＜0.05)。
结论：1.经筛选采用0.3%DMBA丙酮液注射法可诱发形成口腔鳞癌动物模型,缩短实验周期,降低建模成本。
2.经不同剂量的重离子束局部辐照荷瘤金黄地鼠,会影响血清中微量元素的含量,具有一定临床意义。
3.(12)~C~(6+)离子照射对口腔鳞癌组织中的Survivin和Caspase-3蛋白表达产生影响,下调Survivin的表达,间接调节Caspase-3的活性,参与凋亡调控过程。
Objective:To establish hamsters buckle pouch carcinogenesis model by DMBA injection method, The tumor process changes were observed dynamically. To study the effects of trace elements and the expression of apoptosis related genes Survivin, Caspase-3 in hamster buckle pouch carcinogenesis model after carbon ion beams irradiation, so as to provide experimental evidence for Heavy Ion Clinical Therapy of Oral Cancer and risk assessment for Space Radiation.
Materials and Methods:1.This study selected 81 healthy hamsters, they were randomly divided into 3 groups, including the control group (6), the painted group (15), the injected group (60) (also points A, B, C, D, E 5 Groups).With the DMBA acetone solution injection group, The concentration were used to set up for 0.5%,0.4%,0.3%,0.2%,and 0.1%.but the concentration in the painted group was fit for 0.5%. to induce buckle pouch carcinogenesis model in Syrian Golden Hamsters. For the general observation of the model, the body weight has been monitored and the tumor growth rate calculated. Using histological analysis of the similarities and differences in two methods with different pathological stages of.the carcinogenesis process The concentration of injection method by the screening to establish the appropriate carcinogenesis model of oral squamous cell carcinoma.
2. Exposed with carbon ion beam irradiation of cheek pouch carcinoma in hamster, Observation 0,4,6,8,12 Gy dosage of heavy ion beams on the bearing hamster cheek pouch carcinoma of trace elements of content in blood. Application of flame atomic absorption spectroscopy determinated to flexion-extension (Fe) radiographs, copper (Cu), zinc (Zn) and magnesium (Mg), calcium (Ca) the content of trace elements in serum.
3. Immunohistochemical SP method was detected the expression of Survivin and Caspase-3 protein of cheek pouch carcinogenesis in 40 cases bearing golden hamster and to explore on the impact of tumor tissue in Carbon ion beams irradiation.
Results:1 The injection concentrations (0.4%,0.3%,0.2%,0.1%) of DMBA acetone solution have induced the tumors. Respectively, at 13W,9W,12W,16W, the average size is about 0.8cm× 0.6cm×0.5cm; the carcinogenesis rates at 12W were respectively 25%,87%,42%,58%; but 0.5% DMBA solution with painted group, the carcinogenesis rate was 48%,the death rate was 37%. Well differentiated cheek squamous cell carcinoma was obtained at 18W.
2 In the hamsters borne tumor, the contents of Fe, Zn, Cu and Mg in experimental groups with cheek pouch carcinoma were significantly lower than normal group(P<0.05). After irradiated by 0, 4,6,8,12Gy heavy ion beams, the 4Gy group showed a tendency downward. When the irradiation dose reached 6Gy, the contents of Fe, Zn increased. When it reached 12Gy, the contents decreased.. While Cu, Ca and Mg contents in the group at 8Gy reached to their highest value, and had become lowering until 12Gy. All of the results showed a dose-reaction relationship (P<0.05).
3 The number of the expression of positive Survivin protein were 28 among 40 cases in oral squamous cell carcinoma, the positive rate was 70%, but there was no positive individual in normal oral mucosa (0/8); The Caspase-3 expression were 30 among 40 cases, the positive rate was 75% in oral squamous cell carcinoma, and was 100% in normal oral mucosa (8/8). By statistical analysis, we have found there are differences between oral squamous cell carcinoma and normal oral mucosa. After 12C6+ ion irradiation with different doses,Survivin expression was statistically significant (P<0.05) compared with the OSCC group, but the differences of Caspase-3 expression did not occurred. The 12C6+ ion irradiation group compared with OSCC group was not statistically significant (P>0.05).
Conclusions:1 The 0.3% concentration of DMBA acetone solution is more suitable for the formation of oral squamous cell carcinoma model in Golden Hamster in the short term. This method is benefit to shorten the feeding cycle, reduce costs.
2 Exposed with different doses of heavy ion beam irradiation, there are some changes of content in trace elements of serum, which are of clinical significance.
3 12C6+ ion irradiation can reduce the expression of Survivin, indirectly raise the activity of Caspase-3. It reveals to us the 12C6+ ion irradiation may play a critical role in the regulation of the process of cell apoptosis.
引文
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