Subconjunctival Anecortave Acetate, an Angiostatic Steroid, in the Treatment of a Murine Model of Retinoblastoma

Abstract

Abstract: : Purpose: To investigate the vascular response and tumor control efficacy of anecortave acetate, a novel angiostatic steroid, in the subconjunctival treatment of murine transgenic retinoblastoma. Methods: Under ACUC approval, one hundred-twenty 8 week-old SV40 Tag positive mice were treated with subconjunctival anecortave acetate to the right eye only. Group A: Ninety mice received a single 1200, 600, 300, 150 or 75µg/20 µl injection. Six additional mice received a single subconjunctival injection of BSS; left eyes served as untreated controls. Eyes were enucleated at 12, 24 or 36 hours post-treatment. Group B: Thirty mice received serial injections at doses of 1200, 600, 300,150 or 75µg/20 µl twice a week for 3 weeks. Six additional mice received serial subconjunctival injections of BSS; left eyes served as untreated controls. Eyes were enucleated at 16 weeks of age. All eyes were stained with haematoxylin & eosin, PAS, and histopathologically examined for intratumoral vascularity and residual tumor volume. Results: Histological assessment of intratumoral vascularity of eyes treated with a single 1200µg subconjunctival anecortave acetate injection documented a 100% vascular closure rate in comparison to fellow control eyes and untreated controls at both 12 and 24 hours (p<0.01). Tumor vasculature closure was dose and time-dependent. At 12 hours, eyes treated with a single 300µg injection demonstrated 80% vascular closure compared with 98% shutdown in eyes treated with 600µg. No immediate tumor volume reduction was noted for eyes undergoing primary enucleation within 36 hours of single injection treatment. Serial injection documented a dose-dependent inhibition of both tumor vascularity and tumor volume. No evidence of toxicity was noted at any time point or treatment dose. Conclusions: Subconjunctival delivery of anecortave acetate inhibits tumor vasculature and is associated with tumor inhibition in a time and dose-dependent fashion in this murine model of retinoblastoma. Anecortave acetate, an angiostatic steroid, may represent a novel therapy in the treatment of pediatric retinoblastoma.

Keywords: retinoblastoma • oncology • tumors