title: Vitamin D analogs, a new treatment for retinoblastoma: The first Ellsworth Lecture.
abstract: OBJECTIVE
  This lecture honors the memory of Dr. Robert M. Ellsworth, an important figure in the development of current treatments of retinoblastoma (RB), and reviews our studies of vitamin D analogs as treatments for retinoblastoma in two experimental mouse models. We identified vitamin D receptors in retinoblastoma and examined the effectiveness and mechanism of action of these analogs.
  
  
  METHODS
  Reverse-transcriptase polymerase chain reaction (RT-PCR) amplification was used to detect vitamin D receptor mRNAs in human and mouse retinoblastomas. The effectiveness and toxicity of vitamin D(2), calcitriol, and synthetic analogs were studied in the athymic/Y-79 xenograft and transgenic mouse models of RB. Dosing was 5X/week for five weeks. Dose-response studies focused on tumor inhibition; toxicity studies investigated survival and serum calcium. The mechanism of action of vitamin D was investigated using terminal transferase dUTP labeling 3'-overhang ligation to measure apoptosis; immunohistochemistry measured p53-dependent gene expression and cell proliferation.
  
  
  RESULTS
  Vitamin D receptor mRNAs were detectable in Y-79 RB cells, LH beta-Tag tumors, and human RB specimens using RT-PCR. Calcitriol inhibited cell growth in vitro. Calcitriol and vitamin D(2) inhibited in vivo growth in xenograft and transgenic models, but therapeutic levels were toxic due to hypercalcemia. Two analogs, 16,23-D(3) and 1 alpha-OH-D( 2), inhibited tumors in animal models of RB with reduced toxicity. The mechanism of action appears related to increased p53-related gene expression resulting in increased apoptosis.
  
  
  CONCLUSIONS
  16,23-D(3) and 1 alpha-OH-D(2) are effective in tumor reduction in two mouse models of RB with low toxicity. These results warrant initiating phase 1 and phase 2 clinical studies in children.
mesh_terms: D000818:Animals; D017209:Apoptosis; D002117:Calcitriol / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004872:Ergocalciferols; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D002117:Calcitriol