The Radiosensitization Of Homocamptothecin Drug Candidate TOP0618 On Pancreatic Cancer

Part?The sensitization effect of homocamptothecin drug candidateTOP0618 on pancreatic cancer cells in vitroObjective To investigate the radiosensitization effect and its possible mechanism of homocamptothecin drug candidate TOP0618 on pancreatic cancer cell lines PANC-1and MIA PaCa-2.Methods CellTiter-Blue assay and clone forming experiment were used to evaluate the proliferation inhibition function of TOP0618 in PANC-1 and MIA PaCa-2 cells and to calculate IC₅₀.The clone forming experiment tested the radiotherapy sensitization effect.The effects of different treatments on cell cycle and apoptotic rate were detected by flow cytometry.Results The proliferative inhibition of PANC-1 and MIA PaCa-2 cells caused by TOP0618,the IC₅₀0 values were 1.442 and 1.198?M,respectively.TOP0618 increase the radiosensitivity of PANC-1 and MIA PaCa-2 cells after 24h treated with TOP0618?0.2?M?.The sensitivity enhance ratio?SER?were 1.14 and 1.65,respectively.The combination of radiation with TOP0618 changed the phase distribution of the cell cycle,proportion of cells in G₂/M phase increase and apoptosis increase were observed.Conclusion The investigation suggests that TOP0618 has the radiotherapy sensitization effect on pancreatic cancer in vitro.The sensitization mechanism may be relevant to the redistribution of cell-cycle and induction of apoptosis.Part?The sensitization effect of homocamptothecin drug candidate TOP0618 on pancreatic cancer cells in vivoObjective To establish a model of human pancreatic cancer MIA Pa Ca-2 cell line xenograft tumor in nude mice,investigate the radiosensitization effect of TOP0618 in vivo,which will provide experimental basis for future clinical application of pancreatic cancer.Methods The model of 20 nude mice was established with xenograft tumor of MIA Pa Ca-2 in both armpits subcutaneously.20 nude mice were randomly divided,5 mice per group.Normalsaline,TOP0618 12.5 mg/Kg,TOP0618 25 mg/Kg,and positive control drug irinotecan 50 mg/Kg were intraperitoneally injected once every 3 days,respectively.8 treatment distinguished by the right side xenografts treated with irradiation,and the left side xenografts not: the control group?group A?,simple radiation 6Gy group?group B?,low dose TOP0618 group?group C?,low dose TOP0618+ radiation 6Gy group?group D?,high dose TOP0618 group?group E?,high dose TOP0618+ radiation 6Gy group?group F?,Irinotecan as positive control group?group G?,Irinotecan+ radiation 6Gy group?group H?.Xenograft tumors on right side were irradiated a single dose of 6 Gy after 24 hours of the first administration.The volume of each xenograft tumor and the body weight of nude mice were measured twice a week.The growth curve of the xenograft tumors was drawn and the tumor inhibition rate was calculated.The tumor tissue resected at twenty-first day after radiation,HE staining and tunel staining were used to observe the pathological changes and apoptotic of tumor tissue.Results In vivo results showed statistically significant differences in the tumor inhibition rates between groups C and D,and groups E and F?P<0.05?,HE staining and Tunel staining of xenograft tumors showed that the density of tumor cells decreased in each treatment group compared with the control group,the necrosis and apoptosis increased in TOP0618 combined radiotherapy group.Conclusion The investigation suggests that TOP0618 has the radiotherapy sensitization effect on pancreatic cancer in vivo,may be associated with promoting tumor necrosis and tumor cell apoptosis.TOP0618 might be useful as a radiation sensitizer for clinical.The study provides experimental basis of combined TOP0618 with radiotherapy for the treatment of pancreatic cancer.