title: Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis.
abstract: 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.
authors.affiliation: Departments of Ophthalmology, Anatomy and Neurobiology, Pharmaceutical Sciences, Radiology, and Comparative Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA. jsteinl1@uthsc.edu
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Zhang
authors.forename: Karin Emmons
authors.initials: KE
authors.lastname: Thompson
authors.forename: Jordan
authors.initials: J
authors.lastname: Toutounchian
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Yates
authors.forename: Carl
authors.initials: C
authors.lastname: Soderland
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Barrett G
authors.initials: BG
authors.lastname: Haik
authors.forename: J Scott
authors.initials: JS
authors.lastname: Williams
authors.forename: J Scott
authors.initials: JS
authors.lastname: Jackson
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Mandrell
authors.forename: Dianna
authors.initials: D
authors.lastname: Johnson
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D016190:Carboplatin / Q000633:toxicity; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008253:Macaca mulatta; D008558:Melphalan / Q000633:toxicity*; D009504:Neutrophils / Q000378:metabolism; D009880:Ophthalmic Artery / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016209:Interleukin-8; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D016190:Carboplatin; D008558:Melphalan