title: Vascular-targeted TNFα and IFNγ inhibits orthotopic colorectal tumor growth.
abstract: Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. Unfortunately, several clinical studies of relevant cancer therapy did not observe significant response in maximum tolerated dose whether given alone or in combination. We have identified a tumor vasculature homing peptide (TCP-1 peptide) which targets only the vasculature of colorectal tumors but not normal blood vessels in animals and humans. In the current study, the antitumor effect of TCP-1/TNFα and TCP-1/IFNγ alone or in combination was studied in orthotopic colorectal tumor model.
  
  
  
  TCP-1/TNFα and TCP-1/IFNγ recombinant proteins were prepared and i.v. injected to study the in vivo anticancer effect in orthotopic colorectal tumor model. Tumor apoptosis was determined by TUNEL staining and cleaved caspase-3 immunofluorescent staining. Tumor infiltrating lymphocytes were analyzed by immunofluorescent staining and flow cytometry. Western-blot was performed to examine the expression of proteins. Cell apoptosis was measured by Annexin V/PI flow cytometry.
  
  
  
  Targeted delivery of TNFα or IFNγ by TCP-1 peptide exhibited better antitumor activity than unconjugated format by inducing more tumor apoptosis and also enhancing antitumor immunity shown by increased infiltration of T lymphocytes inside the tumor. More importantly, combination therapy of TCP-1/TNFα and TCP-1/IFNγ synergistically suppressed tumor growth and alleviated systematic toxicity associated with untargeted therapy. This combination therapy induced massive apoptosis/secondary necrosis in the tumor.
  
  
  
  Taken together, our data demonstrate TCP-1 is an efficient drug carrier for targeted therapy of colorectal cancer (CRC). TCP-1/TNFα combined with TCP-1/IFNγ is a promising combination therapy for CRC.
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China. jackylizhijie@gmail.com.|Harry Perkins Institute of Medical Research, University of Western Australia, Crawley, WA, 6009, Australia. jackylizhijie@gmail.com.
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Li
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China.
authors.forename: Long Fei
authors.initials: LF
authors.lastname: Li
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China.|School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China.
authors.forename: Zhan Gang
authors.initials: ZG
authors.lastname: Xiao
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China.
authors.forename: Ming Xing
authors.initials: MX
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
authors.forename: Kam Ming
authors.initials: KM
authors.lastname: Chan
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, People's Republic of China. chcho@cuhk.edu.hk.|School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China. chcho@cuhk.edu.hk.
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Colorectal cancer; Drug delivery; IFNγ; TNFα; Vascular targeting