title: Effectiveness of vitamin D analogues in treating large tumors and during prolonged use in murine retinoblastoma models.
abstract: OBJECTIVE
  To investigate the effectiveness of the vitamin D analogues 1,25-(OH)(2)-16-ene-23-yne vitamin D(3) (16,23-D(3)) and 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model.
  
  
  METHODS
  For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm(3). Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed.
  
  
  RESULTS
  In the large-tumor study, tumor volume ratios for the 1alpha-OH-D(2) and 16,23-D(3) groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1alpha-OH-D(2) and 16,23-D(3) groups (P =.15). In the long-term study, the 1alpha-OH-D(2) group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D(3) group and its control. Some toxic effects related to hypercalcemia were seen in both studies.
  
  
  CONCLUSIONS
  In athymic mice in the large-tumor study, both 1alpha-OH-D(2) and 16,23-D(3) were effective in inhibiting tumor growth compared with controls. In the long-term study, 1alpha-OH-D(2) inhibited tumor growth but 16,23-D(3) did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality. Clinical Relevance Use of 1alpha-OH-D(2) inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.
authors.affiliation: Departments of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, F4/344 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-3284, USA. dalbert@wisc.edu
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Albert
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Strugnell
authors.forename: Soesiawati R
authors.initials: SR
authors.lastname: Darjatmoko
authors.forename: Janice M
authors.initials: JM
authors.lastname: Lokken
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Lindstrom
authors.forename: Sarit
authors.initials: S
authors.lastname: Patel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000627:therapeutic use* / Q000633:toxicity; D006934:Hypercalcemia / Q000139:chemically induced; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004872:Ergocalciferols; C042533:1 alpha-hydroxyergocalciferol; D002117:Calcitriol; C064183:Ro 23-7553