May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Effects of Cyclosporin A Monotherapy in Transgenic Murine Retinoblastoma
Author Affiliations & Notes
  • K. R. Van Quill
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • M. Uusitalo
    Ophthalmology, Ophthalmic Pathology Laboratory, Helsinki, Finland
  • J. Smith
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • S. Howard
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • J. Qi
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • J. Perez
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • T. Tsai
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • T. Kivelä
    Ophthalmology, Ophthalmic Pathology Laboratory, Helsinki, Finland
  • J. M. O'Brien
    Ophthalmology, Univ California - San Francisco, San Francisco, California
  • Footnotes
    Commercial Relationships K.R. Van Quill, None; M. Uusitalo, None; J. Smith, None; S. Howard, None; J. Qi, None; J. Perez, None; T. Tsai, None; T. Kivelä, None; J.M. O'Brien, None.
  • Footnotes
    Support NEI RO1 Grant EY13812 and core grant EY02162; Valley Foundation; That Man May See; Research to Prevent Blindness; Ehrnrooth Foundation; Finnish Eye Foundation; Academy of Finland; Nissi Foundation
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1597. doi:https://doi.org/
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    • Get Citation

      K. R. Van Quill, M. Uusitalo, J. Smith, S. Howard, J. Qi, J. Perez, T. Tsai, T. Kivelä, J. M. O'Brien; Effects of Cyclosporin A Monotherapy in Transgenic Murine Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1597. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: High-dose cyclosporin A (CSA) is currently administered as an adjuvant to combination chemotherapy for the treatment of retinoblastoma (RB). CSA has been proposed to act in this setting as a multidrug resistance reversal agent. However, we have previously shown that CSA also induces potent apoptotic effects in RB cell lines at clinically achievable concentrations. These findings suggest that the antitumor effects of CSA therapy in human RB may be mediated, at least in part, by direct cytotoxicity. In the present study, we tested this hypothesis by evaluating the therapeutic effects of CSA monotherapy in LHbeta-Tag transgenic RB mice.

Methods:: To determine maximum tolerated dose, three groups of 10 transgene-negative mice were treated once daily for 4 days with 80, 90, or 100 mg/kg of CSA by intraperitoneal injection. Mice were monitored daily through day 5 for evidence of toxicity. For the treatment study, two randomized groups of twenty-five 14-week-old LHbeta-Tag mice were injected once daily for 4 days with 80 mg/kg CSA or with vehicle control. Mice were killed on day 5, eyes were enucleated and serially sectioned, and ocular tumor burden was quantified by histopathologic analysis.

Results:: Mean tumor burden did not differ significantly between CSA and control groups. Mean tumor burden was 0.52 mm2 (SD, 0.47) per level per two eyes in CSA-treated mice and 0.49 mm2 (SD, 0.47) per level per two eyes in the control group; median tumor burden was 0.30 mm2 (range, 0.024-1.48) and 0.34 mm2 (range, 0.040-2.01), respectively (P = 0.85).

Conclusions:: While these results fail to support our hypothesis that the therapeutic effects of CSA in human RB are mediated by a direct antitumor action, it is also possible that therapeutic effects might be observed in this animal model with modifications in dosing regimen, delivery route, or endpoint selection. We are currently performing longitudinal follow-up studies in a different animal model of RB to assess the effects of CSA exploring these modifications.

Keywords: retinoblastoma • pathology: experimental • tumors 
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