Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma

PURPOSE. To evaluate the effect of subconjunctival injections of combretastatin A-4 phosphate (CA-4P) prodrug treatment on tumor vasculature and growth in an animal model of hereditary retinoblastoma. METHODS. Twenty-four, 12-week-old simian virus-40 T-antigen positive mice received six subconjunctival CA-4P injections at doses of 0.5, 1.0, 1.5, and 2.0 mg delivered at 72-hour intervals to the right eye only. Six control animals received placebo treatment. All animals underwent serial ophthalmic evaluations and were euthanatized at 16 weeks of age, and eyes were obtained for histopathologic examination. Eyes were graded for presence or absence of tumor, delay of tumor growth, and intratumoral vascularity. RESULTS. The use of subconjunctivally injected CA-4P prodrug induced an extensive, dose-dependent decrease in microvessel density and led to significant tumor reduction in treated eyes compared with the placebo control ( P < 0.001). No evidence of corneal, lenticular, choroidal, or retinal toxicity was observed by histopathologic evaluation. CONCLUSIONS. Subconjunctival delivery of CA-4P is associated with extensive dose-dependent reduction in blood vessel count in this murine model of retinoblastoma. A combination treatment of retinoblastoma incorporating CA-4P may allow enhanced tumor reduction enabling a decrease in standard treatment doses of both chemotherapy and external beam radiotherapy.