Vascular-targeted TNFα and IFNγ inhibits orthotopic colorectal tumor growth
Autor: | Lin Zhang, Mingxing Li, Wei Hu, Jing Shen, Chi Hin Cho, Kam Ming Chan, William K.K. Wu, Lan Lu, Zhi Jie Li, Long Fei Li, Zhan Gang Xiao |
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Jazyk: | angličtina |
Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Combination therapy Colorectal cancer medicine.medical_treatment Antineoplastic Agents Apoptosis General Biochemistry Genetics and Molecular Biology Flow cytometry Targeted therapy Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Annexin Cell Line Tumor TNFα medicine Animals Interferon gamma Cell Proliferation Medicine(all) Neovascularization Pathologic medicine.diagnostic_test Tumor Necrosis Factor-alpha business.industry Tumor-infiltrating lymphocytes Biochemistry Genetics and Molecular Biology(all) Research Vascular targeting General Medicine medicine.disease Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Drug delivery Cancer research Tumor necrosis factor alpha Colorectal Neoplasms Peptides business IFNγ medicine.drug |
Zdroj: | Journal of Translational Medicine |
ISSN: | 1479-5876 |
DOI: | 10.1186/s12967-016-0944-3 |
Popis: | Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0944-3) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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