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


METHODS
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 micro g/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-kappaB 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.
Mian
Badar M
BM
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Dinney
Colin P N
CP
Bermejo
Carlos E
CE
Sweeney
Paul
P
Tellez
Carmen
C
Yang
X D
XD
Gudas
Jean M
JM
McConkey
David J
DJ
Bar-Eli
Menashe
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D015536:Down-Regulation; D004338:Drug Combinations; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry* / Q000276:immunology*; D007797:Laminin / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009693:Nucleic Acid Hybridization; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000628:therapy*
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D016209:Interleukin-8; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen; D008156:Luciferases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9