Objective To investigate whether low-dose fractionated radiation(LDFRT) could enhance cisplatin sensitivity in drug-resistant human ovarian cancer cells SKOV3/DDP, and to further explore the underlying mechanism.Metho...Objective To investigate whether low-dose fractionated radiation(LDFRT) could enhance cisplatin sensitivity in drug-resistant human ovarian cancer cells SKOV3/DDP, and to further explore the underlying mechanism.Methods SKOV3/DDP ovarian cancer cells were divided into three groups as follows: control, LDFRT, and conventional-dose radiation groups. Cells from all three groups were treated with different concentrations of cisplatin(0, 1.25, 2.5, 5, 10, and 20 μg/m L) for 48 h. The proliferation inhibition rate was investigated using the cell counting kit 8(CCK8). The rate of apoptosis was determined by flow cytometry(FCM). Protein levels of AKT, P-AKT, GSK-3β, P-GSK-3β, P21, cyclin D1, and P27 were examined by Western blotting. Results As expected, LDFRT significantly reduced the half-maximal inhibitory concentration(IC50) of cisplatin and promoted apoptosis in SKOV3/DDP cells. Moreover, in the LDFRT group, protein levels of P-AKT, P-GSK-3β, and cyclin D1 were markedly decreased, those of P21 and P27 were greatly increased, and total AKT and GSK-3β levels showed no significant difference compared to those in both the control and conventional-dose radiation groups.Conclusion LDFRT sensitizes resistant SKOV3/DDP ovarian cancer cells to cisplatin through inactivation of PI3 K/AKT/GSK-3β signaling.展开更多
Objective To investigate the mechanism of low-dose fractionated radiation on reversing cisplatin resistance in ovarian carcinoma via vascular endothelial growth factor(VEGF) and mammalian target of rapamycin(mTOR) in ...Objective To investigate the mechanism of low-dose fractionated radiation on reversing cisplatin resistance in ovarian carcinoma via vascular endothelial growth factor(VEGF) and mammalian target of rapamycin(mTOR) in vivo.Methods Human cisplatin-resistant ovarian carcinoma cells(SKOV3/DDP) were injected into nude mice to establish ovarian cancer xenografts. The mice were randomly divided into three groups: a control group, a low-dose fractionated radiation(LDRFT) group, and a conventional-dose radiation group. Each group was exposed to 0 cGy, 50 cGy, and 200 cGy radiation, respectively, for 4 weeks, up to a total of 8.0 Gy. Mice in the LDFRT group were irradiated twice daily with 6 hour intermissions on day 1 and 2 of every week for a total of 4 weeks. Conventional-dose group mice were given a single 200 cGy radiation dose on the first day each week for a total of 4 weeks. Maximum horizontal and vertical diameters of the tumors were measured every other day and used to create a tumor growth curve. After 4 weeks of irradiation, we dissected the tumor tissue and calculated the tumor inhibition rate. RT-PCR detected the expression of VEGF and m TOR, and Western blots detected the expression of corresponding proteins.Results Both LDRFT and conventional-dose radiation inhibited the growth of tumor cells, and growth of tumors in the two radiation groups compared with growth in the control group were significantly different(P < 0.05). The rate of tumor inhibition in the LDFRT group(37.5603%) was lower than in the conventionaldose group(47.4446%), but there was no significant difference(P 0.05). Compared with the other two groups, the m RNA expression of VEGF was significantly lower in the LDFRT group(P < 0.05), but there was no obvious difference between the conventional-dose and control groups. There was no obvious difference in the m RNA expression of m TOR among the three groups, but the expression of the protein p-m TOR was lower in the LDFRT group(P < 0.05), as confirmed by Western blotting.Conclusion LDFRT is as effective at inhibiting the growth of tumor cells as conventional-dose radiation. In addition, LDFRT could deregulate the expression of VEGF and p-m TOR, and may therefore play a vital role in reversing cisplatin resistance in ovarian cancer.展开更多
Objective： To investigate the treatment effectiveness and side effects of stereotactic radiotherapy for brain glioma. Methods： From Jun. 1995 to Dec. 1998, 389 cases of brain gliomas were treated by stereotactic rad...Objective： To investigate the treatment effectiveness and side effects of stereotactic radiotherapy for brain glioma. Methods： From Jun. 1995 to Dec. 1998, 389 cases of brain gliomas were treated by stereotactic radiotherapy, among which 151 cases were treated by stereotactic radiosurgery （SRS） and the other 238 cases, by fractionated stereotactic radiotherapy （FSRT）. In the SRS group, the marginal tumor dose was 20 to 30 Gy （median, 2.6 Gy）. One to 6 isocenters （median, 2.48） and 5 to 21 irradiation arcs （median, 8.45） were applied. In the FSRT group, the per-fraction marginal tumor dose was 8 to 12 Gy with 1 to 6 isocenters （median, 2.53）, 6 to 20 irradiation arcs （median, 8.25） and 2-5 fractions delivered everyday or every other day. Results： Three months after treatment, the complete and partial response rates were 13.9% and 45.7% in SRS group respectively. The stable disease rate was 17.2%. The total effective rate was 76.8%. In FSRT group, the complete and partial remission rates were 19.7% and 47.9% respectively. The stable disease rate was 20.6%. The total effective rate was 88.2%. The total effective rate of FSRT group was higher than that in SRS group （X^2=9.874, P=0.020）. The 1-year, 3-year and 5-year survival rate of all patients was 54.3%, 29.3%, 16.5% respectively. The 1-year, 3-year and 5-year survival rate in SRS group and FSRT group was 52.3% vs 26.5%, 11.9% vs 55.5%, and 31.1 vs 19.3% respectively. There was no significant difference between the two groups （X^2=2.16, P=0.1417）. The brain edema caused by the main radiation was more severe in the SRS group than in FSRT group （X^2=4.916, P=0.027）. Conclusion： It is effective for brain glioma to be treated by stereotactic radiotherapy. Compared with SRS, the FSRT has the advantage of good effect and less side response.展开更多
Background:More than 25%of patients with solid cancers develop intracerebral metastases.Aside of surgery,radia-tion therapy(RT)is a mainstay in the treatment of intracerebral metastases.Postoperative fractionated ster...Background:More than 25%of patients with solid cancers develop intracerebral metastases.Aside of surgery,radia-tion therapy(RT)is a mainstay in the treatment of intracerebral metastases.Postoperative fractionated stereotactic RT(FSRT)to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recur-rence.However,FSRT has to be delayed until a sufficient wound healing is attained;hence systemic therapy might be postponed.Neoadjuvant stereotactic radiosurgery(SRS)might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy.Here,we conducted a study to find the maximum tolerated dose(MTD)of neoadjuvant SRS for intracerebral metastases.Methods:This is a single-center,phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital,Technical University of Munich.The rule-based traditional 3+3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied.The primary endpoint is the MTD for which no dose-limiting toxicities(DLT)occur.The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0 continuously during the study until the first follow-up visit(4-6 weeks after surgery).Secondary endpoints include local control rate,survival,immunological tumor characteristics,quality of life(QoL),CTCAE grade of late clinical,neurological,and neurocognitive toxicities.In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS.Depending on the occurrence of DLT up to 72 patients will be enrolled.The recruitment phase will last for 24 months.Discussion:Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity,such as better target volume definition with subsequent higher efficiency of eliminating tumor cells,and lower damage to surrounding healthy tissue,and much-needed systemic chemotherapy could be initiated more rapidly.展开更多
文摘Objective To investigate whether low-dose fractionated radiation(LDFRT) could enhance cisplatin sensitivity in drug-resistant human ovarian cancer cells SKOV3/DDP, and to further explore the underlying mechanism.Methods SKOV3/DDP ovarian cancer cells were divided into three groups as follows: control, LDFRT, and conventional-dose radiation groups. Cells from all three groups were treated with different concentrations of cisplatin(0, 1.25, 2.5, 5, 10, and 20 μg/m L) for 48 h. The proliferation inhibition rate was investigated using the cell counting kit 8(CCK8). The rate of apoptosis was determined by flow cytometry(FCM). Protein levels of AKT, P-AKT, GSK-3β, P-GSK-3β, P21, cyclin D1, and P27 were examined by Western blotting. Results As expected, LDFRT significantly reduced the half-maximal inhibitory concentration(IC50) of cisplatin and promoted apoptosis in SKOV3/DDP cells. Moreover, in the LDFRT group, protein levels of P-AKT, P-GSK-3β, and cyclin D1 were markedly decreased, those of P21 and P27 were greatly increased, and total AKT and GSK-3β levels showed no significant difference compared to those in both the control and conventional-dose radiation groups.Conclusion LDFRT sensitizes resistant SKOV3/DDP ovarian cancer cells to cisplatin through inactivation of PI3 K/AKT/GSK-3β signaling.
基金Supported by a grant from the Province Natural Sciences Foundation of Shandong(No.ZR2016040034)
文摘Objective To investigate the mechanism of low-dose fractionated radiation on reversing cisplatin resistance in ovarian carcinoma via vascular endothelial growth factor(VEGF) and mammalian target of rapamycin(mTOR) in vivo.Methods Human cisplatin-resistant ovarian carcinoma cells(SKOV3/DDP) were injected into nude mice to establish ovarian cancer xenografts. The mice were randomly divided into three groups: a control group, a low-dose fractionated radiation(LDRFT) group, and a conventional-dose radiation group. Each group was exposed to 0 cGy, 50 cGy, and 200 cGy radiation, respectively, for 4 weeks, up to a total of 8.0 Gy. Mice in the LDFRT group were irradiated twice daily with 6 hour intermissions on day 1 and 2 of every week for a total of 4 weeks. Conventional-dose group mice were given a single 200 cGy radiation dose on the first day each week for a total of 4 weeks. Maximum horizontal and vertical diameters of the tumors were measured every other day and used to create a tumor growth curve. After 4 weeks of irradiation, we dissected the tumor tissue and calculated the tumor inhibition rate. RT-PCR detected the expression of VEGF and m TOR, and Western blots detected the expression of corresponding proteins.Results Both LDRFT and conventional-dose radiation inhibited the growth of tumor cells, and growth of tumors in the two radiation groups compared with growth in the control group were significantly different(P < 0.05). The rate of tumor inhibition in the LDFRT group(37.5603%) was lower than in the conventionaldose group(47.4446%), but there was no significant difference(P 0.05). Compared with the other two groups, the m RNA expression of VEGF was significantly lower in the LDFRT group(P < 0.05), but there was no obvious difference between the conventional-dose and control groups. There was no obvious difference in the m RNA expression of m TOR among the three groups, but the expression of the protein p-m TOR was lower in the LDFRT group(P < 0.05), as confirmed by Western blotting.Conclusion LDFRT is as effective at inhibiting the growth of tumor cells as conventional-dose radiation. In addition, LDFRT could deregulate the expression of VEGF and p-m TOR, and may therefore play a vital role in reversing cisplatin resistance in ovarian cancer.
文摘Objective： To investigate the treatment effectiveness and side effects of stereotactic radiotherapy for brain glioma. Methods： From Jun. 1995 to Dec. 1998, 389 cases of brain gliomas were treated by stereotactic radiotherapy, among which 151 cases were treated by stereotactic radiosurgery （SRS） and the other 238 cases, by fractionated stereotactic radiotherapy （FSRT）. In the SRS group, the marginal tumor dose was 20 to 30 Gy （median, 2.6 Gy）. One to 6 isocenters （median, 2.48） and 5 to 21 irradiation arcs （median, 8.45） were applied. In the FSRT group, the per-fraction marginal tumor dose was 8 to 12 Gy with 1 to 6 isocenters （median, 2.53）, 6 to 20 irradiation arcs （median, 8.25） and 2-5 fractions delivered everyday or every other day. Results： Three months after treatment, the complete and partial response rates were 13.9% and 45.7% in SRS group respectively. The stable disease rate was 17.2%. The total effective rate was 76.8%. In FSRT group, the complete and partial remission rates were 19.7% and 47.9% respectively. The stable disease rate was 20.6%. The total effective rate was 88.2%. The total effective rate of FSRT group was higher than that in SRS group （X^2=9.874, P=0.020）. The 1-year, 3-year and 5-year survival rate of all patients was 54.3%, 29.3%, 16.5% respectively. The 1-year, 3-year and 5-year survival rate in SRS group and FSRT group was 52.3% vs 26.5%, 11.9% vs 55.5%, and 31.1 vs 19.3% respectively. There was no significant difference between the two groups （X^2=2.16, P=0.1417）. The brain edema caused by the main radiation was more severe in the SRS group than in FSRT group （X^2=4.916, P=0.027）. Conclusion： It is effective for brain glioma to be treated by stereotactic radiotherapy. Compared with SRS, the FSRT has the advantage of good effect and less side response.
基金This study is funded by the Comprehensive Cancer Center Munich(CCC-M)at the Partner Site“Klinikum rechts der Isar,Technische Universität München/Roman Herzog Cancer Center(RHCCC).
文摘Background:More than 25%of patients with solid cancers develop intracerebral metastases.Aside of surgery,radia-tion therapy(RT)is a mainstay in the treatment of intracerebral metastases.Postoperative fractionated stereotactic RT(FSRT)to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recur-rence.However,FSRT has to be delayed until a sufficient wound healing is attained;hence systemic therapy might be postponed.Neoadjuvant stereotactic radiosurgery(SRS)might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy.Here,we conducted a study to find the maximum tolerated dose(MTD)of neoadjuvant SRS for intracerebral metastases.Methods:This is a single-center,phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital,Technical University of Munich.The rule-based traditional 3+3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied.The primary endpoint is the MTD for which no dose-limiting toxicities(DLT)occur.The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0 continuously during the study until the first follow-up visit(4-6 weeks after surgery).Secondary endpoints include local control rate,survival,immunological tumor characteristics,quality of life(QoL),CTCAE grade of late clinical,neurological,and neurocognitive toxicities.In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS.Depending on the occurrence of DLT up to 72 patients will be enrolled.The recruitment phase will last for 24 months.Discussion:Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity,such as better target volume definition with subsequent higher efficiency of eliminating tumor cells,and lower damage to surrounding healthy tissue,and much-needed systemic chemotherapy could be initiated more rapidly.
