Vitamin D analogs, a new treatment for retinoblastoma

The first Ellsworth Lecture

Daniel Albert, Robert W. Nickells, David M. Gamm, Michele L. Zimbric, Cassandra L. Schlamp, Mary J. Lindstrom, Isabelle Audo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose: 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 D2, 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. Result: Vitamin D receptor mRNAs were detectable in Y-79 RB cells, LHβ-Tag tumors, and human RB specimens using RT-PCR. Calcitriol inhibited cell growthin vitro. Calcitriol and vitamin D2 inhibited in vivo growth in xenograft and transgenic models, but therapeutic levels were toxic due to hypercalcemia. Two analogs, 16,23-D3 and 1α-OH-D2, 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. Conclusion: 16,23-D3 and 1α-OH-D2 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.

Original languageEnglish (US)
Pages (from-to)137-156
Number of pages20
JournalOphthalmic Genetics
Volume23
Issue number3
DOIs
StatePublished - Oct 23 2002
Externally publishedYes

Fingerprint

Retinoblastoma
Vitamin D
Calcitriol Receptors
Calcitriol
Ergocalciferols
Therapeutics
p53 Genes
Reverse Transcriptase Polymerase Chain Reaction
Heterografts
Neoplasms
Apoptosis
Gonadotrophs
Gene Expression
Messenger RNA
Poisons
Hypercalcemia
Transferases
Transgenic Mice
Ligation
Theoretical Models

Keywords

  • Apoptosis
  • p21
  • p53
  • Retinoblastoma
  • Vitamin D analogs

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Ophthalmology
  • Genetics(clinical)

Cite this

Albert, D., Nickells, R. W., Gamm, D. M., Zimbric, M. L., Schlamp, C. L., Lindstrom, M. J., & Audo, I. (2002). Vitamin D analogs, a new treatment for retinoblastoma: The first Ellsworth Lecture. Ophthalmic Genetics, 23(3), 137-156. https://doi.org/10.1076/opge.23.3.137.7883

Vitamin D analogs, a new treatment for retinoblastoma : The first Ellsworth Lecture. / Albert, Daniel; Nickells, Robert W.; Gamm, David M.; Zimbric, Michele L.; Schlamp, Cassandra L.; Lindstrom, Mary J.; Audo, Isabelle.

In: Ophthalmic Genetics, Vol. 23, No. 3, 23.10.2002, p. 137-156.

Research output: Contribution to journalArticle

Albert, D, Nickells, RW, Gamm, DM, Zimbric, ML, Schlamp, CL, Lindstrom, MJ & Audo, I 2002, 'Vitamin D analogs, a new treatment for retinoblastoma: The first Ellsworth Lecture', Ophthalmic Genetics, vol. 23, no. 3, pp. 137-156. https://doi.org/10.1076/opge.23.3.137.7883
Albert, Daniel ; Nickells, Robert W. ; Gamm, David M. ; Zimbric, Michele L. ; Schlamp, Cassandra L. ; Lindstrom, Mary J. ; Audo, Isabelle. / Vitamin D analogs, a new treatment for retinoblastoma : The first Ellsworth Lecture. In: Ophthalmic Genetics. 2002 ; Vol. 23, No. 3. pp. 137-156.
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