Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-κB

Badar M. Mian, Colin P.N. Dinney, Carlos E. Bermejo, Paul Sweeney, Carmen Tellez, X. D. Yang, Jean M. Gudas, David J. McConkey, Menashe Bar-Eli

Research output: Contribution to journalArticle

Abstract

Purpose: We previously demonstrated that overexpression of interleukin 8 (IL-8) in human transitional cell carcinoma (TCC) resulted in increased tumorigenicity and metastasis. This increase in tumor growth and metastasis can be attributed to the up-regulation in the expression and activity of the metalloproteinases MMP-2 and MMP-9. Experimental Design: To investigate whether targeting IL-8 with a fully human anti-IL-8 antibody (ABX-IL8) could be a potential therapeutic strategy for controlling TCC growth, we studied its effects on TCC growth in vitro and in an in vivo mouse model. Human TCC cell lines 253J B-V and UM UC3 (high IL-8 producers), 253J (low IL-8), and 253J transfected with the IL-8 gene (high producer) were used. Results: ABX-IL8 had no effect on TCC cell proliferation in vitro. However, in the orthotopic nude mouse model, after 4 weeks of treatment (100 μg/week, i.p.), a significant decrease in tumor growth of both cell lines was observed. IL-8 blockade by ABX-IL8 significantly inhibited the expression, activity, and transcription of MMP-2 and MMP-9, resulting in decreased invasion through reconstituted basement membrane in vitro. The down-regulation of MMP-2 and MMP-9 in these cells could be explained by the modulation of nuclear factor-κB expression and transcriptional activity by ABX-IL8. Conclusions: Our data point to the potential use of ABX-IL8 as a modality to treat bladder cancer and other solid tumors, either alone or in combination with conventional chemotherapy or other antitumor agents.

Original languageEnglish (US)
Pages (from-to)3167-3175
Number of pages9
JournalClinical Cancer Research
Volume9
Issue number8
StatePublished - Aug 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Mian, B. M., Dinney, C. P. N., Bermejo, C. E., Sweeney, P., Tellez, C., Yang, X. D., Gudas, J. M., McConkey, D. J., & Bar-Eli, M. (2003). Fully human anti-interleukin 8 antibody inhibits tumor growth in orthotopic bladder cancer xenografts via down-regulation of matrix metalloproteases and nuclear factor-κB. Clinical Cancer Research, 9(8), 3167-3175.