Increased hypoxia following vessel targeting in a murine model of retinoblastoma

Hinda Boutrid, Yolanda Pin ̃a, Colleen M. Cebulla, William J. Feuer, Theodore J. Lampidis, Maria Elena Jockovich, Timothy G. Murray

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The purpose of this study was to evaluate the effects of vessel targeting and chemotherapy agents on inducing hypoxic regions in LHBETATAG murine retinal tumors. Methods. Twelve- and 16-week-old LHBETATAG transgenic retinoblastoma mice were treated with periocular injections to the right eye only of saline (n = 42), anecortave acetate (a single injection; 300 fxg/20;xL; n = 42), or carboplatin (two injections per week for 3 weeks; 62.5 fxg/20;xL; n = 42). Eyes were enucleated 1 day, 1 week, and 1 month after injection. To assess hypoxia, mice received 60 mg/kg pimonidazole via intraperitoneal injection. Eyes were enucleated, and tumor sections were analyzed. Results. Levels of hypoxia significantly increase in 16-week-old animals 1 day and 1 week after treatment with anecortave acetate, a known angiostatic agent. Eyes treated with anecortave acetate showed a 28% (P < 0.001) increase in hypoxic regions in comparison with the saline-treated control group 1 day after injection and a 17% (P < 0.001) increase 1 week after injection. In early tumors of 12-week-old animals, levels of hypoxia increased by 2.0% (P = 0.011) 1 day after anecortave acetate injection compared to controls. Levels of hypoxia significantly decrease in 16-week-old animals 1 week and 1 month after treatment with carboplatin, a chemotherapeutic agent. Eyes treated with carboplatin showed a 21.7% (P = 0.017) decrease in hypoxic regions in comparison with the saline-treated control group 1 week after injection and a 4.51% (P < 0.001) decrease 1 month after injection. In early tumors of 12-week-old animals, levels of hypoxia decreased by 0.0429% (P < 0.001) 1 month after carboplatin injection compared with controlsConclusions. Treatment with a vessel-targeting agent results in changes in the tumor microenvironment as early as 1 day after treatment. By increasing hypoxia in tumors, vessel-targeting agents can be combined with glycolytic inhibitors which have been shown previously to target hypoxic regions in this transgenic model. This approach may have benefits for children with this disease and should be further investigated.

Original languageEnglish (US)
Pages (from-to)5537-5543
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number12
DOIs
StatePublished - Dec 2009

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Boutrid, H., Pin ̃a, Y., Cebulla, C. M., Feuer, W. J., Lampidis, T. J., Jockovich, M. E., & Murray, T. G. (2009). Increased hypoxia following vessel targeting in a murine model of retinoblastoma. Investigative Ophthalmology and Visual Science, 50(12), 5537-5543. https://doi.org/10.1167/iovs.09-3702