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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

Reduction in the percentage of tumor hypoxia following different doses of treatment with rapamycin. The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage of hypoxia in comparison with the groups treated with 0.00333 and 0.167 mg/kg of rapamycin (P = 0.024 and P = 0.052, respectively).Note: *Denotes statistical significant percentage difference in comparison with the groups treated with 0.00333 and 0.167 mg/kg.Abbreviation: DMSO, dimethyl sulfoxide.
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f3-opth-5-337: Reduction in the percentage of tumor hypoxia following different doses of treatment with rapamycin. The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage of hypoxia in comparison with the groups treated with 0.00333 and 0.167 mg/kg of rapamycin (P = 0.024 and P = 0.052, respectively).Note: *Denotes statistical significant percentage difference in comparison with the groups treated with 0.00333 and 0.167 mg/kg.Abbreviation: DMSO, dimethyl sulfoxide.

Mentions: The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002) (Figures 2 and 3). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage 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). There was no difference between the highest doses of rapamycin (3.33 and 6.67 mg/kg) for the percentage of intratumoral hypoxia (P = 0.997). There is a significant correlation between tumor burden and the percentage of hypoxia (P < 0.001; Spearmen non-parametric correlation, r = 0.725).


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)

Reduction in the percentage of tumor hypoxia following different doses of treatment with rapamycin. The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage of hypoxia in comparison with the groups treated with 0.00333 and 0.167 mg/kg of rapamycin (P = 0.024 and P = 0.052, respectively).Note: *Denotes statistical significant percentage difference in comparison with the groups treated with 0.00333 and 0.167 mg/kg.Abbreviation: DMSO, dimethyl sulfoxide.
© Copyright Policy
Related In: Results  -  Collection

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

f3-opth-5-337: Reduction in the percentage of tumor hypoxia following different doses of treatment with rapamycin. The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage of hypoxia in comparison with the groups treated with 0.00333 and 0.167 mg/kg of rapamycin (P = 0.024 and P = 0.052, respectively).Note: *Denotes statistical significant percentage difference in comparison with the groups treated with 0.00333 and 0.167 mg/kg.Abbreviation: DMSO, dimethyl sulfoxide.
Mentions: The percentage of hypoxia is significantly different between the rapamycin doses (P < 0.002) (Figures 2 and 3). Eyes treated with rapamycin at 3.33 mg/kg showed a significant decrease in the percentage 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). There was no difference between the highest doses of rapamycin (3.33 and 6.67 mg/kg) for the percentage of intratumoral hypoxia (P = 0.997). There is a significant correlation between tumor burden and the percentage of hypoxia (P < 0.001; Spearmen non-parametric correlation, r = 0.725).

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