Antitumor Activity Of Novel Camptothecin Derivative YCJ100

Aims: Camptothecin(CPT),an anti-tumor drug,was first isolated from Chinese Camptotheca acuminata in 1966 by Wall et al.Camptothecin has significant cytotoxic activity and inhibits the growth of tumor cells by binding to topisorease I and blocking the DNA replication.However,application of camptothecin was restricted by its low solubility,severe side effects and instability in vivo.Thus,novel camptothecin derivatives with high solubility and stability but low toxixicty are desired.To this end,we synthesized a series of camptothecin analogs using various modifiction strategies.Then we screened these derivatives for their antitumor activities and found that YCJ100 has the highest cytotoxicity among those chemicals.We next evaluated its anti-tumor activity,molecular mechanism and systemic toxicity.Methods: The anti-tumor activiey and toxicy of YCJ100 were evaluated both in vitro and in vivo.In vitro,we used MTT assay to detect the anti-tumor activities of YCJ100 in tumor cell lines,and then calculated IC50 s.The effects of YCJ100 on cell cycle and apoptosis were determined using western blot and flow cytometry.Cell proliferation was detected using Ed U staining.Anti-tumor mechanism of YCJ100 was also investigated using topoisomerase I activity assay.In vivo,the anti-tumor activity of YCJ100 was evaluated in primary liver cancer and xenograft tumor model,respectively.Systemic toxicity of YCJ100 was evaluated in mice with a single dose injection.Results: MTT results indicated that YCJ100,with IC50 s from 0.5 to 2.8 μM,has significant higher cytotoxicity compared with topotecan,with IC50 s from 0.7 to4.2 μM.In HepG2 and SW1990 cells,YCJ100 treatment killed more cells compared with Topotecan at a same conentration.Flow cytometry and western blot analysis showed that YCJ100 killed the cells by blocking the cell cycle in G2 / M phase and inducing apoptosis.EDU staining showed YCJ100 inhibited cell proliferation in HepG2 and SW1990 cells as well.YCJ100 can inhibit topoisomerase I activity in both cell-free system and the cellular system.In primary liver cancer mice,YCJ100 reduced the tumor burden by 70% compared with Topotecan with an inhibition ratio of 44%。In xenograft model,YCJ100 inhibited the tumor growth by 55% compared with Topotecan at 40%.YCJ100 showed minor toxicity to hemopoietic system,liver and kidney.Conclusion: The camptothecin derivative YCJ100 had superior anti-tumor activity but low systemic toxicity,meriting further preclinical evaluation and potential clinical development.