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T.G. Murray, M.E. Jockovich, F. Suarez, E. Hernandez, W. Feuer; Combined Angiostatic and Periocular Chemotherapy Using Combretastatin A4P And Carboplatin in the Treatment of LHBETATAG Transgenic Murine Model of Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2290.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate tumor control efficacy and to determine optimal drug delivery scheduling for the combined treatment of murine transgenic retinoblastoma, using Combretastatin A4P (CA4P), an angiostatic agent, and Carboplatin.
All experiments in this study were conducted in accordance with ARVO guidelines. A. 10 week–old LHBETATAG mice (six mice per group) were treated with subtherapeutic doses of Carboplatin (62.5 µg/20µl) delivered via six bi–weekly subconjunctival injections to right eyes only; left eyes served as untreated controls. CA4P (1mg/20µl) was delivered one day prior or one day following Carboplatin injections. B. 10 week–old LHBETATAG mice (six mice per group) were treated with 62.5 µg/20µl of Carboplatin delivered via three weekly subconjunctival injections. CA4P (1mg/20µl) was delivered one day prior or one day following Carboplatin injections. Control mice received either drug alone or saline. Eyes were analyzed at 16 weeks of age.
Histological assessment of tumor volume suggests a dose and drug delivery scheduling dependent tumor response to the combined treatment. Disrupting vessels prior to chemotherapy results in inhibition of tumor control; disrupting vessels following chemotherapy results in an additive, though not statistically significant effect in the control of tumor burden. Functional assays suggest that treatment with CA4P results in vascular closure one day post–delivery and vessel reperfusion one week later. To test the hypothesis that functional vessels are necessary for chemotherapy delivery injections were performed one week intervals. A statistically significant (p<0.05) reduction in tumor burden is detected when weekly injections of carboplatin were performed following vessel closure with CA4P.
Subconjunctival delivery of CA4P combined with Carboplatin effectively inhibits intraocular tumor burden in the LHBETATAG model of retinoblastoma. Vessel disruption prior to chemotherapy results in inhibition of chemotherapy efficacy. This combined treatment affords the dual benefit of closing intratumoral blood flow while potentially increasing intraocular drug concentration. This treatment modality may represent a novel strategy for the treatment of pediatric retinoblastoma.
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