Gelatinase expression in retinoblastoma: Modulation of LHBETATAG retinal tumor development by anecortave acetate

PURPOSE. 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 μg) was delivered to the right eyes of 10-week-old LHBETATAG 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_BETAT_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.