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Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice.

Kropp J, Roti Roti EC, Ringelstetter A, Khatib H, Abbott DH, Salih SM - PLoS ONE (2015)

Bottom Line: Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult.During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR.While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.

ABSTRACT
Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients.

No MeSH data available.


Related in: MedlinePlus

Dexra pretreatment prevents DXR-induced reduction in ovary weight.Mean weight measured in milligrams (mg). The graph plots mean ovarian weight for each treatment group at 8 months of age. Error bars indicate the SE of the mean ovary weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 14 Ctl (vehicle control), 4 DXR, 17 Dexra1:DXR1 (1:1 mg ratio), 15 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 11 DexraC10, where n represents the total number of animals in each group at the end of the study where both ovaries used for statistical analysis. The control and DXR-only treatment groups adapted from [27].
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pone.0142588.g007: Dexra pretreatment prevents DXR-induced reduction in ovary weight.Mean weight measured in milligrams (mg). The graph plots mean ovarian weight for each treatment group at 8 months of age. Error bars indicate the SE of the mean ovary weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 14 Ctl (vehicle control), 4 DXR, 17 Dexra1:DXR1 (1:1 mg ratio), 15 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 11 DexraC10, where n represents the total number of animals in each group at the end of the study where both ovaries used for statistical analysis. The control and DXR-only treatment groups adapted from [27].

Mentions: To determine whether ovarian mass decreased following DXR chemotherapy, surviving breeder mice were euthanized at 8 months of age, and ovaries were removed and weighed. The mean weights of ovaries from DXR mice were 6.96 ± 1.19 mg, a ~35% decrease (p = 0.009) from control ovarian weights (10.73 ± 0.54 mg, Fig 7). The bursa surrounding the ovaries of DXR mice were often filled with excess fluid, a phenomenon not observed in mice in any other treatment group (data not quantified). Dexra1:DXR1 treated mice had a mean ovarian weight of 10.03 ± 0.45 mg that was comparable to control, while showing a trend (p = 0.06) towards a greater ovarian weight than DXR alone. Dexra10:DXR1 treated animals exhibited intermediate ovarian weights at 9.7 ± 0.6 mg that were not different from either control or DXR-treated animals (p = 0.40). DexraC1 and DexraC10 mice had mean ovarian weights similar to those of control at 11.68 ± 0.58 mg and 10.27 ± 0.44 mg, respectively. These data demonstrate that the lower Dexra dose may provide better shielding from DXR-induced loss of ovarian weight.


Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice.

Kropp J, Roti Roti EC, Ringelstetter A, Khatib H, Abbott DH, Salih SM - PLoS ONE (2015)

Dexra pretreatment prevents DXR-induced reduction in ovary weight.Mean weight measured in milligrams (mg). The graph plots mean ovarian weight for each treatment group at 8 months of age. Error bars indicate the SE of the mean ovary weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 14 Ctl (vehicle control), 4 DXR, 17 Dexra1:DXR1 (1:1 mg ratio), 15 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 11 DexraC10, where n represents the total number of animals in each group at the end of the study where both ovaries used for statistical analysis. The control and DXR-only treatment groups adapted from [27].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4636352&req=5

pone.0142588.g007: Dexra pretreatment prevents DXR-induced reduction in ovary weight.Mean weight measured in milligrams (mg). The graph plots mean ovarian weight for each treatment group at 8 months of age. Error bars indicate the SE of the mean ovary weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 14 Ctl (vehicle control), 4 DXR, 17 Dexra1:DXR1 (1:1 mg ratio), 15 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 11 DexraC10, where n represents the total number of animals in each group at the end of the study where both ovaries used for statistical analysis. The control and DXR-only treatment groups adapted from [27].
Mentions: To determine whether ovarian mass decreased following DXR chemotherapy, surviving breeder mice were euthanized at 8 months of age, and ovaries were removed and weighed. The mean weights of ovaries from DXR mice were 6.96 ± 1.19 mg, a ~35% decrease (p = 0.009) from control ovarian weights (10.73 ± 0.54 mg, Fig 7). The bursa surrounding the ovaries of DXR mice were often filled with excess fluid, a phenomenon not observed in mice in any other treatment group (data not quantified). Dexra1:DXR1 treated mice had a mean ovarian weight of 10.03 ± 0.45 mg that was comparable to control, while showing a trend (p = 0.06) towards a greater ovarian weight than DXR alone. Dexra10:DXR1 treated animals exhibited intermediate ovarian weights at 9.7 ± 0.6 mg that were not different from either control or DXR-treated animals (p = 0.40). DexraC1 and DexraC10 mice had mean ovarian weights similar to those of control at 11.68 ± 0.58 mg and 10.27 ± 0.44 mg, respectively. These data demonstrate that the lower Dexra dose may provide better shielding from DXR-induced loss of ovarian weight.

Bottom Line: Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult.During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR.While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.

ABSTRACT
Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients.

No MeSH data available.


Related in: MedlinePlus