Gelatinase expression in retinoblastoma: modulation of LH(BETA)T(AG) retinal tumor development by anecortave acetate.
OBJECTIVE
Gelatinases, matrix metalloproteinase (MMP)-2, and MMP-9 are known for their importance in angiogenesis and tumor biology. The purpose of this study was to test the hypothesis that anecortave acetate (AA) decreases transgenic retinoblastoma (RB) tumor burden by modulating gelatinase activity.


METHODS
To assess the possible gelatinase modulation after AA treatment, a single subconjunctival injection of AA (300 microg) was delivered to the right eyes of 10-week-old LH(BETA)T(AG) mice. Eyes were evaluated for gelatinase expression and activity by gel and in situ zymography at 24 hours, 48 hours, and 1 week after treatment.


RESULTS
Gel zymography of whole eye extracts and in situ zymography of retinal tumors showed strong gelatinase expression and activity within transgenic RB tumors. AA treatment in RB transgenic mice resulted in a significant decrease of gelatinase activity 1 week after AA treatment. Surprisingly, there was an initial transient upregulation of MMP-9 activity in whole eye extracts at 24 and 48 hours after AA treatment in both LH(BETA)T(AG) transgenic and wild-type mice. This increase was not observed in the tumors.


CONCLUSIONS
As suggested by our data, inhibition of gelatinase activity appears to be a mechanism of action of AA. AA treatment results in a decrease in gelatinase activity that correlates with the significant decrease in tumor burden shown by the authors' previous studies. However, the significance of the initial, transient upregulation of gelatinase by AA injection is unknown, and further studies are warranted. Combining antiangiogenic agents with multiple mechanisms of action has the potential to enhance RB tumor control.
Bajenaru
M Livia
ML
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida 33101, USA.
Piña
Yolanda
Y
Murray
Timothy G
TG
Cebulla
Colleen M
CM
Feuer
William
W
Jockovich
Maria-Elena
ME
Marin Castaño
Maria-Encarna
ME
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D019084:Fluorescent Antibody Technique, Indirect; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011244:Pregnadienediols / Q000627:therapeutic use*; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D011244:Pregnadienediols; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C418047:anecortave acetate