July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Efficacy, Toxicity and Biodistribution of Intra-arterial vs. Intravenous Chemotherapy in a Rabbit Retinoblastoma Model
Author Affiliations & Notes
  • Anthony B Daniels
    Department of Ophthalmology, Vanderbilt Eye Institute, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Michael T Froehler
    Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Janene M Pierce
    Department of Ophthalmology, Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Amy H Nunnally
    Department of Ophthalmology, Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Ivan Bozic
    Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
  • Yuankai Tao
    Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
  • Yaofang Zhang
    Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
  • M. Wade Calcutt
    Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
  • Liping Du
    Biostatistics, Vanderbilt University, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kelli L Boyd
    Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Debra L Friedman
    Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Ann Richmond
    Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, United States
    Cancer Biology Program, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Anthony Daniels, Vanderbilt University Medical Center (P); Michael Froehler, Blockade Medical (C), Control Medical (C), Medtronic (C), Medtronic (F), Microvention (F), Penumbra (F), Stryker (C), Stryker (F); Janene Pierce, None; Amy Nunnally, None; Ivan Bozic, None; Yuankai Tao, Leica Microsystems (R), Vanderbilt University (P); Yaofang Zhang, None; M. Calcutt, None; Liping Du, None; Kelli Boyd, None; Debra Friedman, Vanderbilt University Medical Center (P); Ann Richmond, None
  • Footnotes
    Support  National Eye Institute grant NIH/NEI 1K08EY027464-01 [ABD], Research to Prevent Blindness Career Development Award [ABD], Career Starter Grant from the Knights Templar Eye Foundation [ABD], by an unrestricted departmental grant from Research to Prevent Blindness to the Vanderbilt Department of Ophthalmology and Visual Sciences, by a Department of Veterans Affairs Senior Research Career Scientist Award [AR], and by the Vanderbilt Ingram Cancer Center Support Grant (CA68485) for core facilities.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1642. doi:
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      Anthony B Daniels, Michael T Froehler, Janene M Pierce, Amy H Nunnally, Ivan Bozic, Yuankai Tao, Yaofang Zhang, M. Wade Calcutt, Liping Du, Kelli L Boyd, Debra L Friedman, Ann Richmond; Efficacy, Toxicity and Biodistribution of Intra-arterial vs. Intravenous Chemotherapy in a Rabbit Retinoblastoma Model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1642.

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

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Abstract

Purpose : We previously described the first small animal model of intra-arterial chemotherapy (IAC) and our retinoblastoma xenograft rabbit model. Here, we directly compare pharmacokinetics following intravenous (IV) and IAC, their respective toxicities, and efficacy of each in treating retinoblastoma in vivo in rabbits.

Methods : Tissue drug levels were determined by serial sacrifice of rabbits following IAC or IV melphalan (0.4mg/kg) or carboplatin (50mg) (n=18 rabbits/drug/route). Toxicity was assessed (n=24 rabbits) by electroretinography, OCT, OCTA, fluorescein angiography, and histopathology, prior to and 5-weeks post-treatment with either IAC melphalan (0.4-1.2mg/kg), IV melphalan, or IV carboplatin/etoposide/vincristine, with weekly blood counts. Efficacy of each treatment was assessed against tumor xenografts in vivo in rabbits eyes by measuring induced apoptosis of tumor cells.

Results : Maximum carboplatin concentration (Cmax) in the treated eye was 1434.8μM for retina with IAC vs. 10.7μM with IV (134-fold, p<0.05 [Wilcoxon]), and in vitreous was 419.1μM with IAC vs. 1.02μM with IV (419-fold, p<0.05). Plasma Cmax was similar regardless of route (p=1.0) and Cmax in IAC-untreated (contralateral) eye was similar to IV treatment (p>0.1), suggesting drug enters the contralateral (“untreated”) eye by systemic recirculation following unilateral IAC. Areas-under-the-curve analyses, and results with IAC vs. IV melphalan, matched the above findings. IAC melphalan caused no evidence of vascular occlusions or retinal damage at standard doses. Electroretinographic reductions were dose dependent. With supratherapeutic melphalan (regardless of route), transient neutropenia occurred, but not at standard doses. Typical doses of IAC melphalan (3.6mg) caused apoptosis of tumor cells in vivo in our xenograft model (including vitreous seeds). IV chemotherapy was unable to treat retinoblastoma xenografts.

Conclusions : IAC achieves higher retinal and vitreous levels in the treated eye than does IV chemotherapy. However, plasma drug levels and drug levels in the contralateral eye are the same for IAC and IV, suggesting full systemic exposure to IAC drug. Toxicity is low at standard doses, and appears drug- and dose-specific, not related to the IAC procedure itself. Orthotopic retinoblastoma xenografts can be effectively treated by IAC in our model, paving the way for future drug discovery research.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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