title: Factor VII light chain-targeted lidamycin targets tissue factor-overexpressing             tumor cells for cancer therapy.
abstract: The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers make TF an ideal target for cancer therapy. Here, we report an energized fusion protein, hlFVII-LDP-AE, which can be used for cancer therapy and is composed of a human Factor VII light chain (hlFVII) conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE). hlFVII-LDP-AE binds with specificity to TF expressed on tumor cells, resulting in internalization of the fusion protein and cytotoxicity induced by the LDM domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was examined in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and in vivo with a BALB/c nude mouse xenograft model of the human lung cancer line NCI-H292. hlFVII-LDP-AE caused chromatin condensation and cleavage of genomic DNA in NCI-H292 cells. In the MTT assays, the IC50 value of hlFVII- LDP-AE was 0.19 nM. In the in vivo tests, after two intravenous injections of hlFVII-LDP-AE at a dose of 0.6 mg/kg, the growth rate of the lung tumor xenograft was reduced to 15% of the control rate, and there was no excessive loss of body weight and inflammatory response in the mice. These findings suggest that hlFVII-LDP-AE is efficacious and tolerated in the mouse model of NCI-H292 human lung cancer examined and could have broad clinical applicability for treating cancer patients.
authors: Center for Functional Genomics and Bioinformatics, College of                     Life Science, Sichuan University, Chengdu, Sichuan 610064, P.R. China.
authors: Qing
authors: Q
authors: Zhang
authors: Xiu-Jun
authors: XJ
authors: Liu
authors: Lian
authors: L
authors: Hu
authors: Dong-Sheng
authors: DS
authors: Liao
authors: Yan-Bo
authors: YB
authors: Zheng
authors: Yong-Su
authors: YS
authors: Zhen
authors: Xu
authors: X
authors: Song
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000617:Aminoglycosides / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D053281:Enediynes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000617:Aminoglycosides; D000970:Antineoplastic Agents; D053281:Enediynes; D011993:Recombinant Fusion Proteins; C573542:hlFVII-LDP-AE fusion protein; C058024:C 1027; D005167:Factor VII; D013925:Thromboplastin