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Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors.

Piña Y, Decatur C, Murray T, Houston S, Gologorsky D, Cavalcante M, Cavalcante L, Hernandez E, Celdran M, Feuer W, Lampidis T - Clin Ophthalmol (2011)

Bottom Line: Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively).The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means).The number of neovessels was not significantly different between both groups (P = 0.092).

View Article: PubMed Central - PubMed

Affiliation: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA;

ABSTRACT

Purpose: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LH(BETA)T(AG) retinal tumors.

Methods: This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LH(BETA)T(AG) retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.

Results: Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).

Conclusion: Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LH(BETA)T(AG) retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.

No MeSH data available.


Related in: MedlinePlus

Effect of rapamycin on mature blood vessels. Neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on reducing tumor burden and hypoxia (ie, 3.33 mg/kg). Although the amount of both neo- and mature vessels decreased following treatment with rapamycin, only the amount of small-caliber, mature vessels decreased significantly (P = 0.015). DAPI stain (blue) for all the cell nuclei, endoglin stain (green) for neovessels, and α-sma stain (red) for mature blood vessels. Pictures were obtained at 200× high power field.Note: *Arrows indicate neovessels that do not overlap with mature vessels.Abbreviations: DAPI, 4′,6′-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.
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f5-opth-5-337: Effect of rapamycin on mature blood vessels. Neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on reducing tumor burden and hypoxia (ie, 3.33 mg/kg). Although the amount of both neo- and mature vessels decreased following treatment with rapamycin, only the amount of small-caliber, mature vessels decreased significantly (P = 0.015). DAPI stain (blue) for all the cell nuclei, endoglin stain (green) for neovessels, and α-sma stain (red) for mature blood vessels. Pictures were obtained at 200× high power field.Note: *Arrows indicate neovessels that do not overlap with mature vessels.Abbreviations: DAPI, 4′,6′-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.

Mentions: To assess the impact of periocular administration of rapamycin on blood vessels, the amount of neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on the reduction of tumor burden and hypoxia (ie, 3.33 mg/kg). Blood vessels were broken down by vessel caliber (ie, small and large).31 The percentage of mature vessels was significantly lower in the rapamycin treated versus the vehicle control group (P = 0.015; equal variances assumed, t-test for equality of means) (Figures 4 and 5). The percentage of neovessels was not significantly different between the rapamycin treated and the vehicle control group (P = 0.092). This change was mainly due to the small-caliber blood vessels with a reduction of 41.1% for mature vessels versus 70.5% for neovessels compared with the vehicle control (P < 0.001). There were no significant changes for large-caliber vessels for neither neo- nor mature vessels compared with the vehicle control (101% and 54.7%, respectively).


Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors.

Piña Y, Decatur C, Murray T, Houston S, Gologorsky D, Cavalcante M, Cavalcante L, Hernandez E, Celdran M, Feuer W, Lampidis T - Clin Ophthalmol (2011)

Effect of rapamycin on mature blood vessels. Neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on reducing tumor burden and hypoxia (ie, 3.33 mg/kg). Although the amount of both neo- and mature vessels decreased following treatment with rapamycin, only the amount of small-caliber, mature vessels decreased significantly (P = 0.015). DAPI stain (blue) for all the cell nuclei, endoglin stain (green) for neovessels, and α-sma stain (red) for mature blood vessels. Pictures were obtained at 200× high power field.Note: *Arrows indicate neovessels that do not overlap with mature vessels.Abbreviations: DAPI, 4′,6′-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3065577&req=5

f5-opth-5-337: Effect of rapamycin on mature blood vessels. Neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on reducing tumor burden and hypoxia (ie, 3.33 mg/kg). Although the amount of both neo- and mature vessels decreased following treatment with rapamycin, only the amount of small-caliber, mature vessels decreased significantly (P = 0.015). DAPI stain (blue) for all the cell nuclei, endoglin stain (green) for neovessels, and α-sma stain (red) for mature blood vessels. Pictures were obtained at 200× high power field.Note: *Arrows indicate neovessels that do not overlap with mature vessels.Abbreviations: DAPI, 4′,6′-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.
Mentions: To assess the impact of periocular administration of rapamycin on blood vessels, the amount of neovessels and mature vessels were analyzed for the rapamycin dose with the highest impact on the reduction of tumor burden and hypoxia (ie, 3.33 mg/kg). Blood vessels were broken down by vessel caliber (ie, small and large).31 The percentage of mature vessels was significantly lower in the rapamycin treated versus the vehicle control group (P = 0.015; equal variances assumed, t-test for equality of means) (Figures 4 and 5). The percentage of neovessels was not significantly different between the rapamycin treated and the vehicle control group (P = 0.092). This change was mainly due to the small-caliber blood vessels with a reduction of 41.1% for mature vessels versus 70.5% for neovessels compared with the vehicle control (P < 0.001). There were no significant changes for large-caliber vessels for neither neo- nor mature vessels compared with the vehicle control (101% and 54.7%, respectively).

Bottom Line: Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively).The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means).The number of neovessels was not significantly different between both groups (P = 0.092).

View Article: PubMed Central - PubMed

Affiliation: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA;

ABSTRACT

Purpose: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LH(BETA)T(AG) retinal tumors.

Methods: This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LH(BETA)T(AG) retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.

Results: Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).

Conclusion: Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LH(BETA)T(AG) retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.

No MeSH data available.


Related in: MedlinePlus