Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis

Jena J. Steinle, Qiuhua Zhang, Karin Emmons Thompson, Jordan Toutounchian, Charles Yates, Carl Soderland, Fan Wang, Clinton F. Stewart, Barrett G. Haik, J. Scott Williams, J. Scott Jackson, Timothy D. Mandrell, Dianna Johnson, Matthew Wilson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2439-2445
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number4
DOIs
StatePublished - Apr 1 2012

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Leukostasis
Ophthalmic Artery
Melphalan
Blood Vessels
Endothelial Cells
Inflammation
Drug Therapy
Retinoblastoma
Carboplatin
Pharmaceutical Preparations
Chemotactic Factors
Vascular Endothelium
Interleukin-8
Drug Interactions
Primates
Cell Movement
Retina
Monocytes
Cell Proliferation
Apoptosis

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis. / Steinle, Jena J.; Zhang, Qiuhua; Thompson, Karin Emmons; Toutounchian, Jordan; Yates, Charles; Soderland, Carl; Wang, Fan; Stewart, Clinton F.; Haik, Barrett G.; Scott Williams, J.; Scott Jackson, J.; Mandrell, Timothy D.; Johnson, Dianna; Wilson, Matthew.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 4, 01.04.2012, p. 2439-2445.

Research output: Contribution to journalArticle

Steinle, JJ, Zhang, Q, Thompson, KE, Toutounchian, J, Yates, C, Soderland, C, Wang, F, Stewart, CF, Haik, BG, Scott Williams, J, Scott Jackson, J, Mandrell, TD, Johnson, D & Wilson, M 2012, 'Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis', Investigative Ophthalmology and Visual Science, vol. 53, no. 4, pp. 2439-2445. https://doi.org/10.1167/iovs.12-9466
Steinle, Jena J. ; Zhang, Qiuhua ; Thompson, Karin Emmons ; Toutounchian, Jordan ; Yates, Charles ; Soderland, Carl ; Wang, Fan ; Stewart, Clinton F. ; Haik, Barrett G. ; Scott Williams, J. ; Scott Jackson, J. ; Mandrell, Timothy D. ; Johnson, Dianna ; Wilson, Matthew. / Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 4. pp. 2439-2445.
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AU - Thompson, Karin Emmons

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AU - Yates, Charles

AU - Soderland, Carl

AU - Wang, Fan

AU - Stewart, Clinton F.

AU - Haik, Barrett G.

AU - Scott Williams, J.

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AU - Mandrell, Timothy D.

AU - Johnson, Dianna

AU - Wilson, Matthew

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N2 - 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.

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