(from abstract). The PI proposes to continue with studies regarding the molecular biology of retinoblastoma, focusing on the evaluation of chemotherapeutic and chemopreventative actions of vitamin D analogs (Specific Aim 1) and the identification of the mechanism of action of these compounds on retinoblastoma (Specific Aim 2). The subaims are: (I a) Determine the effectiveness and toxicity of Ia-hydroxyvitamin D2 (Ia-hydroxy-D2), and compare its potency and toxicity to 1,25-dihydroxy-16-ene-23-yne-vitarnin D3 (16,23-D3) in the treatment of transgenic and athvmic models of retinoblastoma. (Ib) Study the ability of these compounds to induce reduction tumor mass. (Ic) Compare the effectiveness of these analogs to standard chemotherapy used in the treatment of retinoblastoma and evaluate the effectiveness of vitamin D analogs as adjuvant therapy. (Id) Determine the effectiveness of these compounds on the midbrain tumors in """"""""trilateral"""""""" retinoblastoma. (Ie) Evaluate the emergence of drug-resistant subpopulations of retinoblastoma cells.
Sub aims to Specific Aim 2 are: (2a) Study the relationship of vitamin D receptors to drug therapy effectiveness. (2b) Determine the mechanism by which cell proliferation arrest is mediated by vitamin D analogs with regard to cell cycle proliferation and cell death. (2c) Establish whether the mechanism of tumor growth arrest is regulated by p53 -dependent gene expression. (2d) Determine whether I a-hydroxy-D2 and 16,23 -D3 inhibit angiogenesis in a transgenic mouse model. These studies will complete the pre-clinical investigation of the efficacy of vitamin D analogs for human treatment.
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