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T. G. Murray, H. Boutrid, E. Hernandez, W. Shi, W. Feuer, M. E. Jockovich; Antiangiogenic Therapy for Retinoblastoma: Effect of Tumor Burden and Dose Schedule in the Murine LH BETATAG Transgenic Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):22. doi: https://doi.org/.
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To investigate the effect of varying tumor burden on the efficacy of anti-angiogenic therapy in the LHBETATAG murine transgenic retinoblastoma. We have previously reported the efficacy of anecortave acetate on tumor burden at 10 weeks of age. We hypothesize that tumor burden will impact the efficacy of anecortave acetate.
The study protocol was approved by the University of Miami, IACUC. All experiments were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. LHBETATAG mice of 4, 10 and 16 weeks of age (six mice per group) were treated with a single subconjunctival injection of anecortave acetate (150, 300 and 600µg/20µl) to right eyes only. Control mice received subconjunctival injections of vehicle. Eyes were analyzed at 22 weeks of age for residual tumor burden.
Results from this experiment show that a greater reduction in tumor burden is detected when mice are treated at a younger age, which correlates with decreased tumor burden. A linear regression model relating tumor burden to dose and age at treatment (r=0.61, p<0.001) found a highly significant (p<0.001) increase in tumor burden with age at treatment. Further, a highly statistically significant negative interaction between dose and age at treatment (p=0.001) demonstrates that while the highest dose (600µg) was most effective at 16 weeks, this was not the case for eyes treated at earlier treatment times.
Previous results suggest that blood vessel maturation, which initiates at 12 weeks of age in these retinal tumors, limits vessel targeting therapy. Results also indicate that mice with advanced disease, 16 weeks of age, have large regions of hypoxia. These hypoxic regions are potentially less susceptible to vessel targeting agents given their anaerobic metabolism. We hypothesize that efficacy of vessel targeting therapy is limited in advanced retinoblastoma tumors seemingly to the degree of vessel maturation and large areas of hypoxia detected in large tumors. Thus, vessel targeting may be combined with pericyte targeting therapy and/or glycolytic inhibitors may improve the efficacy of treatment for advanced retinoblastoma tumors.
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