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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 decrease in pup weight.Weight measured in grams (g) on PND1 and represented as mean weight for each treatment. Error bars indicate the SE of the mean pup weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 939 pups for Control (vehicle control), 175 for DXR, 524 for Dexra1:DXR1 (1:1 mg ratio dose), 703 for Dexra10:DXR1 (10:1 mg ratio dose), 712 for DexraC1, and 428 for DexraC10. The control and DXR-only treatment groups adapted from [27].
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pone.0142588.g005: Dexra pretreatment prevents DXR-induced decrease in pup weight.Weight measured in grams (g) on PND1 and represented as mean weight for each treatment. Error bars indicate the SE of the mean pup weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 939 pups for Control (vehicle control), 175 for DXR, 524 for Dexra1:DXR1 (1:1 mg ratio dose), 703 for Dexra10:DXR1 (10:1 mg ratio dose), 712 for DexraC1, and 428 for DexraC10. The control and DXR-only treatment groups adapted from [27].

Mentions: On postnatal day one, birth weights were collected from each pup to test the hypothesis that Dexra treatment of dams maintained pup weight despite DXR insult. Pups born to DXR-treated dams had weights lower than vehicle control-treated animals, 1.53 ± 0.02 vs. 1.80 ± 0.01 g, respectively (Fig 5; p<0.05, one-way ANOVA, Bonferroni means comparison). Pups derived from dams treated with Dexra1:DXR1 had a mean birth weight of 1.72 ± 0.01 g that was not different from controls (Fig 5; p = 0.3, one-way ANOVA), while exhibiting a trend (p<0.06) toward increased mean birth weight compared to DXR alone. In contrast, pups derived from dams treated with Dexra10:DXR1 had a mean pup weight of 1.67 ± 0.01 g that was lower than control (Fig 5; p<0.05, one-way ANOVA). As the focus of this study was on low dose Dexra protection, it is worth noting that fewer animals were enrolled in the high dose Dexra protection arm. Dexra alone was well tolerated, as pups derived from DexraC1 and DexraC10 dams weighed an average of 1.74 and 1.73 g, respectively, and were not significantly different from pups born to vehicle control dams (Fig 5). These data demonstrate that the lower dose of Dexra (Dexra1:DXR1) improved pup birth weight in dams treated with DXR. The higher dose ratio (Dexra10:DXR1) currently used for cardioprotection, however, was less effective in preventing weight loss.


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 decrease in pup weight.Weight measured in grams (g) on PND1 and represented as mean weight for each treatment. Error bars indicate the SE of the mean pup weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 939 pups for Control (vehicle control), 175 for DXR, 524 for Dexra1:DXR1 (1:1 mg ratio dose), 703 for Dexra10:DXR1 (10:1 mg ratio dose), 712 for DexraC1, and 428 for DexraC10. 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.g005: Dexra pretreatment prevents DXR-induced decrease in pup weight.Weight measured in grams (g) on PND1 and represented as mean weight for each treatment. Error bars indicate the SE of the mean pup weight. Letters above data points represent groups that significantly differ from one another, one-way ANOVA with Bonferroni means comparison, n = 939 pups for Control (vehicle control), 175 for DXR, 524 for Dexra1:DXR1 (1:1 mg ratio dose), 703 for Dexra10:DXR1 (10:1 mg ratio dose), 712 for DexraC1, and 428 for DexraC10. The control and DXR-only treatment groups adapted from [27].
Mentions: On postnatal day one, birth weights were collected from each pup to test the hypothesis that Dexra treatment of dams maintained pup weight despite DXR insult. Pups born to DXR-treated dams had weights lower than vehicle control-treated animals, 1.53 ± 0.02 vs. 1.80 ± 0.01 g, respectively (Fig 5; p<0.05, one-way ANOVA, Bonferroni means comparison). Pups derived from dams treated with Dexra1:DXR1 had a mean birth weight of 1.72 ± 0.01 g that was not different from controls (Fig 5; p = 0.3, one-way ANOVA), while exhibiting a trend (p<0.06) toward increased mean birth weight compared to DXR alone. In contrast, pups derived from dams treated with Dexra10:DXR1 had a mean pup weight of 1.67 ± 0.01 g that was lower than control (Fig 5; p<0.05, one-way ANOVA). As the focus of this study was on low dose Dexra protection, it is worth noting that fewer animals were enrolled in the high dose Dexra protection arm. Dexra alone was well tolerated, as pups derived from DexraC1 and DexraC10 dams weighed an average of 1.74 and 1.73 g, respectively, and were not significantly different from pups born to vehicle control dams (Fig 5). These data demonstrate that the lower dose of Dexra (Dexra1:DXR1) improved pup birth weight in dams treated with DXR. The higher dose ratio (Dexra10:DXR1) currently used for cardioprotection, however, was less effective in preventing weight loss.

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