Reversal effect of thalidomide on drug resistance of daratumumab in transplanted myeloma in nude mice
Objective To observe the reversal effect of thalidomide on drug resistance of daratumumab in transplant-ed myeloma in nude mice and to explore the related mechanism.Methods Balb/c nude mice were divided into the blank group(n=10),model group(n=10),and experimental group(n=10),respectively.The MPC-11 cells of plasmacy-toma in the logarithmic growth phase were inoculated into the right axilla of nude mice in the model group and experimental group to establish the models of subcutaneous myeloma in nude mice.In the experimental group,144 mg/kg was injected subcutaneously on the 1st and 8th days after tumor formation,and 15 mg/kg thalidomide was given to the stomach at 48 h after the first subcutaneous injection of daratumumab,once a day;while in the blank group and model group,distilled wa-ter was given daily.In the experimental group,NK cell depletion was detected at different time points after daratumumab injection;in the experimental group,we detected the NK cell changes before the first dose of daratumumab,and NK cell depletion point after daratumumab injection on day 3 of thalidomide and at the second dose of daratumumab.After the ex-periment,flow cytometry was used to detect NK cells and CD38 expression in each group.ELISA was used to detect inter-leukin(IL)-15,IFN-γ,and tumor necrosis factor(TNF)-α in nude mice serum.Results After injection of daratumum-ab,the number of NK cells in the experimental group increased at first,reached the highest at 24 h,and then decreased.The number of NK cells in the model group was lower than that in the blank group,while the number of NK cells in the ex-perimental group was higher than that in the model group(all P<0.01).The expression of CD38 in the model group was higher than that in the blank group,while the expression of CD38 in the experimental group was lower than that in the mod-el group(both P<0.01).The numbers of NK cells in nude mice of the experimental group were 3.25±0.23,12.65±1.27,26.48±0.66,and 37.67±1.45,respectively,before the first administration of daratumumab,at the time point of depletion of NK cells after injection of thalidomide,on the third day after administration of thalidomide and before the second administration of daratumumab,showing an increasing trend.The serum levels of IL-15,IFN-γ,and TNF-α in the model group were higher than those in the blank group(all P<0.05),and the levels of IL-15 and IFN-γ in the experimen-tal group were higher than those in the blank group(all P<0.01).Conclusions The depletion of NK cells is one of the important reasons for the drug resistance of myeloma cells to daratumumab.Thalidomide may reverse the drug resistance of transplanted myeloma cells to daratumumab by alleviating the depletion of NK cells and regulating the expression of inflam-matory factors.
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