In vivo assessment of novel intra-arterial and intravitreal chemotherapy compounds using a tumor-bearing rabbit model of intra-arterial chemotherapy: Efficacy without toxicity

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.