fosbretabulin and Retinoblastoma

To evaluate the mechanism and timing of retinal tumor cell death in the LH(BETA)T(AG) mouse model of retinoblastoma after treatment with vascular targeting therapies and conventional therapies (focal chemotherapy and radiation).. For vascular targeting therapy, 12- or 16-week-old mice were treated with a single subconjunctival injection of either anecortave acetate (300 microg) or combretastatin A4 (1.5 mg). Eyes were analyzed at 1 day and 1 week after treatment. Tumor cell death was evaluated using TUNEL assays or immunofluorescence analysis of activated caspase 3 to detect apoptosis. Histopathologic analysis was performed to identify areas of necrosis. For conventional therapy, LH(BETA)T(AG) mice were treated with six serial subconjunctival injections of focally delivered carboplatin chemotherapy (100 microg/delivery) or hyperfractionated external beam radiotherapy (EBRT; 15 Gy total dose). Cell death was analyzed by TUNEL assay.. The highest levels of apoptotic cell death were seen 1 day after treatment in all treatment groups compared with vehicle controls. At 1 week after treatment, apoptotic cell death remained significantly elevated in the EBRT and carboplatin groups, but not after vessel targeting therapy. No significant necrosis was detected by histology in tumors of treated or of control eyes.. Conventional therapies (focal carboplatin chemotherapy and EBRT) and vascular targeting agents significantly increase cell death through apoptosis, while not having a significant effect on necrosis in this murine model of retinoblastoma. These studies will aid in the optimization of delivery schemes of combined treatment modalities.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Carboplatin; Caspase 3; Disease Models, Animal; Endothelium, Vascular; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Neovascularization, Pathologic; Pregnadienediols; Radiotherapy, Conformal; Retinal Neoplasms; Retinoblastoma; Stilbenes; Time Factors

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.. 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.. 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.. 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.

Topics: Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents; Conjunctiva; Disease Models, Animal; Dose-Response Relationship, Drug; Injections; Mice; Mice, Transgenic; Neovascularization, Pathologic; Prodrugs; Retinal Neoplasms; Retinoblastoma; Stilbenes