A Preliminary Study on Combination Therapy of Artemisinin Dimer Oxime and Topotecan against Nonsmall Cell Lung Cancer in Mice

摘要

Background:Artemisinin dimer oxime-dimer molecule synthesized from artemisinin possesses high bioavailability and marked in vitro anticancer activities against solid tumor-derived cell lines,endothelial cell proliferation,migration,and angiogenic processes.Numerous murine models have been developed to study human cancer.The most widely used models are the human tumor xenograft mouse model.Materials and Methods:In this study,human tumor cells (NCI-H640,1 × 107 in 100 μL) are implanted subcutaneously,or 1 × 107 in 50 μL in the thoracic cavity,in athymic nude mice (nu/nu).The implanted cells were allowed to grow for 10 days before initiation of drug treatment (dimer oxime and topotecan,ip).Tumor volume and thoracic/body weight ratio were recorded.Results:We successfully established subcutaneous and thoracic xenografts with human nonsmall cell lung cancer cell line xenografts in athymic nude mice in only 10 days.Using these models,we attempted treatment of xenografts with topotecan-a known anticancer drug and artemisinin dimer oxime or combination of these two drugs.Combination therapy showed a significant reduction in tumor volume and tumor/body weight.Treatments with combination of topotecan and dimer oxime resulted in the reduced mortality rates in comparison with untreated mice.Conclusions:Xenograft tumor models are useful for preclinical screening of new pharmacophores.From this preliminary study,it appears that combination of dimer oxime and topotecan may be used as chemotherapeutic agents against nonsmall cell lung cancer.Further studies are needed to evaluate other combination treatment regimens as well as the mechanism(s) of action.