AIM: To explore effects of telomerase RNA-targeting phosphorothioate antisense oligodeoxynucleotides (PS-ASODN) on growth of human gastrointestinal stromal tumors transplanted in mice. METHODS: A SCID mouse model for ...AIM: To explore effects of telomerase RNA-targeting phosphorothioate antisense oligodeoxynucleotides (PS-ASODN) on growth of human gastrointestinal stromal tumors transplanted in mice. METHODS: A SCID mouse model for transplantation of human gastrointestinal stromal tumors (GISTs) was established using tumor cells from a patient who was diagnosed with GIST and consequently had been treated with imatinib. GIST cells cultured for 10 passages were used for inoculation into mice. Transfection of PS-ASODN was carried out with Lipotap Liposomal Transfection Reagent. GISTs that subsequently developed in SCID mice were subjected to intratumoral injection once daily from day 7 to day 28 postinoculation, and mice were divided into the following four groups according to treatment: PS-ASODN group (5.00 μmoL/L of oligonucleotide, each mouse received 0.2 mL once daily); imatinib group (0.1 mg/g body weight); liposome negative control group (0.01 mL/g); and saline group (0.01 mL/g). On day 28, the mice were sacrificed, and tumor attributes including weight and longest and shortest diameters were measured. Tumor growth was compared between treatment groups, and telomerase activity was measured by enzyme-linked immunosorbent assay. Apoptosis was examined by flow cytometry. Real-time polymerase chain reaction was used to detect expression of the mRNA encoding the apoptosis inhibition B-cell leukemia/lymphoma 2 (bcl-2 ) gene. RESULTS: In the PS-ASODN group, tumor growth was inhibited by 59.437%, which was markedly higher than in the imatinib group (11.071%) and liposome negative control group (2.759%) [tumor inhibition=(mean tumor weight of control group - mean tumor weight of treatment group)/(mean tumor weight of control group) × 100%]. Telomerase activity was significantly lower (P < 0.01) in the PS-ASODN group (0.689 ± 0.158) compared with the imatinib group (1.838 ± 0.241), liposome negative control group (2.013 ± 0.273), and saline group (2.004 ± 0.163). Flow cytometry revealed that the apoptosis rate of tumor cells treated with PS-ASODN was 20.751% ± 0.789%, which was higher (P < 0.01) than that of the imatinib group (1.163% ± 0.469%), liposome negative control group (1.212% ± 0.310%), and saline group (1.172% ± 0.403%). Expression of bcl-2 mRNA in the transplanted GISTs was markedly downregulated (P < 0.01) in the PS-ASODN group (7.245 ± 0.739) compared with the imatinib group (14.153 ± 1.618) and liposome negative control group (16.396 ± 1.351).CONCLUSION: PS-ASODN can repress GIST growth, mediated perhaps by inhibition of telomerase activity and downregulation of bcl-2 expression.展开更多
Surgery used to be the only therapy for gastric cancer, and since its ability to cure gastric cancer was the focus of attention, less attention was paid to functionpreserving surgery in gastric cancer, though it was s...Surgery used to be the only therapy for gastric cancer, and since its ability to cure gastric cancer was the focus of attention, less attention was paid to functionpreserving surgery in gastric cancer, though it was studied for gastroduodenal ulcer. Maki et al developed pylorus-preserving gastrectomy for gastric ulcer in 1967. At the same time, the definition of early gastric cancer(EGC) was being considered, histopathological investigations of EGC were carried out, and the validity of modified surgery was sustained. After the development of H2-blockers, the number of operations for gastroduodenal ulcers decreased, and the number of EGC patients increased simultaneously. As a result, the indications for pylorus-preserving gastrectomy for EGC in the middle third of the stomach extended, and various alterations were added. Since then, many kinds of function-preserving gastrectomies have been performed and studied in other fields of gastric cancer, and proximal gastrectomy, jejunal pouch interposition, segmental gastrectomy, and local resection have been performed. On the other hand, from the overall perspective, it can be said that endoscopic resection, which was launched at almost the same time, is the ultimate function-preserving surgery under the current circumstances. The current function-preserving gastrectomies that are often performed and studied are pylorus-preserving gastrectomy and proximal gastrectomy. The reasons for this are that these procedures that can be performed with systemic lymph node dissection, and they include three important elements:(1) reduction of the extent of gastrectomy;(2) preservation of the pylorus; and(3) preservation of the vagal nerve. In addition, these operations are more likely to be performed with a laparoscopic approach as minimally invasive surgery. Of the above-mentioned three elements, reduction of the extent of gastrectomy is the most important in our view. Therefore, we should try to reduce the extent of gastrectomy if curability of the gastric cancer can still be achieved. However, if we preserve a wider residual stomach in functionpreserving gastrectomy, we should pay attention to the development of metachronous gastric cancer.展开更多
基金Supported by The Natural Science Foundation of Zhejiang Province, No. Y201016273
文摘AIM: To explore effects of telomerase RNA-targeting phosphorothioate antisense oligodeoxynucleotides (PS-ASODN) on growth of human gastrointestinal stromal tumors transplanted in mice. METHODS: A SCID mouse model for transplantation of human gastrointestinal stromal tumors (GISTs) was established using tumor cells from a patient who was diagnosed with GIST and consequently had been treated with imatinib. GIST cells cultured for 10 passages were used for inoculation into mice. Transfection of PS-ASODN was carried out with Lipotap Liposomal Transfection Reagent. GISTs that subsequently developed in SCID mice were subjected to intratumoral injection once daily from day 7 to day 28 postinoculation, and mice were divided into the following four groups according to treatment: PS-ASODN group (5.00 μmoL/L of oligonucleotide, each mouse received 0.2 mL once daily); imatinib group (0.1 mg/g body weight); liposome negative control group (0.01 mL/g); and saline group (0.01 mL/g). On day 28, the mice were sacrificed, and tumor attributes including weight and longest and shortest diameters were measured. Tumor growth was compared between treatment groups, and telomerase activity was measured by enzyme-linked immunosorbent assay. Apoptosis was examined by flow cytometry. Real-time polymerase chain reaction was used to detect expression of the mRNA encoding the apoptosis inhibition B-cell leukemia/lymphoma 2 (bcl-2 ) gene. RESULTS: In the PS-ASODN group, tumor growth was inhibited by 59.437%, which was markedly higher than in the imatinib group (11.071%) and liposome negative control group (2.759%) [tumor inhibition=(mean tumor weight of control group - mean tumor weight of treatment group)/(mean tumor weight of control group) × 100%]. Telomerase activity was significantly lower (P < 0.01) in the PS-ASODN group (0.689 ± 0.158) compared with the imatinib group (1.838 ± 0.241), liposome negative control group (2.013 ± 0.273), and saline group (2.004 ± 0.163). Flow cytometry revealed that the apoptosis rate of tumor cells treated with PS-ASODN was 20.751% ± 0.789%, which was higher (P < 0.01) than that of the imatinib group (1.163% ± 0.469%), liposome negative control group (1.212% ± 0.310%), and saline group (1.172% ± 0.403%). Expression of bcl-2 mRNA in the transplanted GISTs was markedly downregulated (P < 0.01) in the PS-ASODN group (7.245 ± 0.739) compared with the imatinib group (14.153 ± 1.618) and liposome negative control group (16.396 ± 1.351).CONCLUSION: PS-ASODN can repress GIST growth, mediated perhaps by inhibition of telomerase activity and downregulation of bcl-2 expression.
文摘Surgery used to be the only therapy for gastric cancer, and since its ability to cure gastric cancer was the focus of attention, less attention was paid to functionpreserving surgery in gastric cancer, though it was studied for gastroduodenal ulcer. Maki et al developed pylorus-preserving gastrectomy for gastric ulcer in 1967. At the same time, the definition of early gastric cancer(EGC) was being considered, histopathological investigations of EGC were carried out, and the validity of modified surgery was sustained. After the development of H2-blockers, the number of operations for gastroduodenal ulcers decreased, and the number of EGC patients increased simultaneously. As a result, the indications for pylorus-preserving gastrectomy for EGC in the middle third of the stomach extended, and various alterations were added. Since then, many kinds of function-preserving gastrectomies have been performed and studied in other fields of gastric cancer, and proximal gastrectomy, jejunal pouch interposition, segmental gastrectomy, and local resection have been performed. On the other hand, from the overall perspective, it can be said that endoscopic resection, which was launched at almost the same time, is the ultimate function-preserving surgery under the current circumstances. The current function-preserving gastrectomies that are often performed and studied are pylorus-preserving gastrectomy and proximal gastrectomy. The reasons for this are that these procedures that can be performed with systemic lymph node dissection, and they include three important elements:(1) reduction of the extent of gastrectomy;(2) preservation of the pylorus; and(3) preservation of the vagal nerve. In addition, these operations are more likely to be performed with a laparoscopic approach as minimally invasive surgery. Of the above-mentioned three elements, reduction of the extent of gastrectomy is the most important in our view. Therefore, we should try to reduce the extent of gastrectomy if curability of the gastric cancer can still be achieved. However, if we preserve a wider residual stomach in functionpreserving gastrectomy, we should pay attention to the development of metachronous gastric cancer.
