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
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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