July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
In vivo assessment of novel intra-arterial and intravitreal chemotherapy compounds using a tumor-bearing rabbit model of intra-arterial chemotherapy: Efficacy without toxicity
Author Affiliations & Notes
  • Anthony B Daniels
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Carley M Bogan
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Michael T. Froehler
    Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Jessica V. Kaczmarek
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Janene M. Pierce
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Amy H. Nunnally
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kelli L. Boyd
    Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yuankai Tao
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
    Department of Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Sheau-chiann Chen
    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Liping Du
    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Debra Friedman
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Ann Richmond
    Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, United States
    Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Anthony Daniels, Spectrum Pharmaceuticals (F), Vanderbilt (P); Carley Bogan, None; Michael Froehler, Balt USA (C), Control Medical (C), Medtronic (C), Medtronic (F), Microvention (F), NeurVana (C), Penumbra (F), Stryker (C), Stryker (F), Viz.ai (C); Jessica Kaczmarek, None; Janene Pierce, None; Amy Nunnally, None; Kelli Boyd, None; Yuankai Tao, Duke University (P); Sheau-chiann Chen, None; Liping Du, None; Debra Friedman, None; Ann Richmond, None
  • Footnotes
    Support  Career Development Award from the Research to Prevent Blindness Foundation [ABD], by the National Eye Institute grant NIH/NEI 5K08EY027464-02 [ABD], by Spectrum Pharmaceuticals through an investigator-initiated study, and by an unrestricted departmental grant from Research to Prevent Blindness to the Vanderbilt Department of Ophthalmology and Visual Sciences. This work was also supported by a Department of Veterans Affairs Senior Research Career Scientist Award [AR], and the Vanderbilt Ingram Cancer Center Support Grant (CA68485) for core facilities. It was also supported by P41 GM103391-06 and by the National Center for Research Resources, Grant UL1RR024975-01, now at the National Center for Advancing Translational Sciences (2 UL1 TR000445-06). None of the sponsors had any role in the design or execution of the studies or in evaluation of the data.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1322. doi:
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    • Get Citation

      Anthony B Daniels, Carley M Bogan, Michael T. Froehler, Jessica V. Kaczmarek, Janene M. Pierce, Amy H. Nunnally, Kelli L. Boyd, Yuankai Tao, Sheau-chiann Chen, Liping Du, Debra Friedman, Ann Richmond; In vivo assessment of novel intra-arterial and intravitreal chemotherapy compounds using a tumor-bearing rabbit model of intra-arterial chemotherapy: Efficacy without toxicity. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1322.

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

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Abstract

Purpose : We recently described the first small animal (rabbit) model of intra-arterial chemotherapy (IAC), a rabbit retinoblastoma xenograft model with retinal tumors and vitreous seeds, and an extensive toxicity assessment platform for this model. Here, we use of this combined model (rabbit IAC, tumor xenograft, toxicity assessment platform) to assess the efficacy and toxicity of various traditional chemotherapies and novel molecularly-targeted antineoplastic agents.

Methods : For IAC, each drug was injected (various doses were studied) via microcatheter. For intravitreal experiments, 3 weekly injections of each drug/dose were performed. For both IAC and intravitreals, retinal structure and function were assessed by ERG, photography, FA, OCT, and OCTA, both before and after treatment. For assessment of efficacy of intravenous, intra-arterial, or intravitreal chemotherapy, human WERI-Rb1 cells were xenografted into rabbit eyes. Assessment of efficacy against vitreous seeds was by both direct quantification of residual seed burden and by assessment of apoptosis induction.

Results : Toxicity was dose-dependent and drug-specific. The clinically-observed toxicities of intra-arterial melphalan (retinopathy and vasculopathy) and carboplatin (vasogenic edema) could be recapitulated. Intravitreal melphalan caused retinopathy with reduction of retinal function beween 65-90% (by ERG). Various doses of intravitreal topotecan were studied. 15μg topotecan (corresponding to 30μg in humans) caused no statistically significant ERG reductions. A new class of inhibitor targeting gene expression in retinoblastoma was studied by intravitreal injections at various doses. A dose of 350μg caused no statistically significant ERG reductions, while 700μg caused minor ERG redutions. 15μg topotecan and 350μg of the new inhibitor were both equally effective to melphalan at eradicating vitreous seeds (93% reduction with melphalan [p=0.004], 97% reduction with topotecan [p=0.009], 95% reduction with new inhibitor [p<0.001]).

Conclusions : For the first time, intra-arterial chemotherapies, alone or in combination with intravitreal chemotherapies, can be studied for both efficacy and toxicity in a preclinical model. Alternative agents with excellent efficacy but minimal toxicity have been identified using our drug discovery system.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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