Intra-Ophthalmic Artery Chemotherapy Triggers Vascular Toxicity through Endothelial Cell Inflammation and Leukostasis

Abstract

1,6,9 PURPOSE. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. METHODS.To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC.RESULTS. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. CONCLUSIONS.These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies. (Invest Ophthalmol Vis Sci.

Intra‐arterial chemotherapy for retinoblastoma. Challenges of a prospective study

“…Other subtle variations in the technique, such as the penetration of the microcatheter into the artery (1-2 cm reported in Muen et al (2012); just 1-2 mm into the ostium in our study) may explain some of the differences as well. Studies in vitro and in non-tumour bearing animals suggest that melphalan might be toxic to the retinal endothelial cells (Wilson et al 2011b;Steinle et al 2012). Histopathological findings indicative of vessel occlusion and intravascular foreign body reactions were found in enucleated eyes from IAM-treated patients both in our study and in a previous one (Eagle et al 2011).…”

Choroidal Ischemia Sparing the Watershed Zone following Intra-Arterial Chemotherapy for Retinoblastoma

“…However, the watershed zone can be vulnerable to ischemia, especially during times of severe systemic hypotension, because the most distal arteriolar branches have the lowest perfusion pressure [8]. The main choroidal watershed zone lies between the areas supplied by the medial and temporal PCAs, typically found on either side of or encompassing the optic disc and as a vertical strip superiorly and inferiorly to the optic disc [6, 9]. Here, we describe a unique case of choroidal ischemia secondary to IAC in which the watershed zone was spared.…”

“…Studies in a nonhuman primate model revealed endothelial cell smudging, leukostasis, and terminal vascular occlusion following treatment with IAC using melphalan or carboplatin [9]. There is laboratory evidence that high doses of melphalan in vitro cause cell death in this manner, while low doses inhibit cell death [9].…”

“…There is laboratory evidence that high doses of melphalan in vitro cause cell death in this manner, while low doses inhibit cell death [9]. If an area, such as the watershed zone, is exposed to only a very small amount of downstream melphalan, it could actually be more likely to survive compared to those areas upstream that receive the highest dose.…”

Retrobulbar ocular blood flow changes measured by colour Doppler imaging after intra-arterial chemotherapy in retinoblastoma

“…The vascular toxicity may be related to the pH, the pulsatile delivery or the chemotherapeutic drugs used 17. In a non-human primate model, the retinal arterioles revealed smudging of the endothelial cells and their basement membranes with terminal vessel occlusion 18.…”