Vessel Targeting Increases Hypoxia in a Murine Model of Retinoblastoma
Hinda Boutrid 1*,
Yolanda Pina 2,
Colleen Cebulla 2,
William J. Feuer 2,
Theodore J. Lampidis 3,
Maria-Elena Jockovich 2,
and
Timothy Murray 4
1 Ophthalmology, University of Miami, PO Box 016880, Miami, Florida, 33101, United States
2 Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
3 Cell Biology and Anatomy, Univesity of Miami Miller School of Medicine, Miami, Florida, United States
4 Bascom Palmer Eye Institute, Miami, Florida, United States
* To whom correspondence should be addressed. E-mail: hboutrid{at}yahoo.com.
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Abstract |
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Purpose: 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; 300µg/20µl; n = 42), or carboplatin (biweekly injections for three weeks; 62.5µg/20µl; n = 42). Eyes were enucleated 1-day, 1-week and 1-month post injection. To assess hypoxia, mice received 60 mg/kg of pimonidazole via intraperitoneal injection. Eyes were enucleated and tumor sections were analyzed.
Results: Levels of hypoxia significantly increase in 16 week-old animals one day and one week following 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 one day post injection and a 17% (P < 0.001) increase one week post injection. Levels of hypoxia significantly decrease in 16 week-old animals one week (21.7%, P = 0.017) and one month following treatment (4.51%, P < 0.001) with carboplatin, a chemotherapeutic agent.
Conclusions: Treatment with a vessel targeting agent results in changes in the tumor microenvironment as early as one day post 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.
Key Words:
confocal microscopy, hypoxia, retinoblastoma, transgenic animals
