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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 prevents DXR-induced dsDNA breaks in ovarian cells.Neutral comet assay was performed on the indicated cell types. Panel A quantifies dsDNA breaks in granulosa-enriched cell populations at time points from 0–24 h post-DXR injection. Panel B quantifies dsDNA breaks in stromal/thecal-enriched cell populations at time points from 0–24 h post-DXR injection. Panel C bar graph quantifies dsDNA breaks in oocytes at 24 h post-DXR injection. n = 3 mice/group/point, per replicate, 4 replicates. * p< 0.05, one-way ANOVA. The control and DXR-only treatment groups adapted from [27].
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pone.0142588.g001: Dexra prevents DXR-induced dsDNA breaks in ovarian cells.Neutral comet assay was performed on the indicated cell types. Panel A quantifies dsDNA breaks in granulosa-enriched cell populations at time points from 0–24 h post-DXR injection. Panel B quantifies dsDNA breaks in stromal/thecal-enriched cell populations at time points from 0–24 h post-DXR injection. Panel C bar graph quantifies dsDNA breaks in oocytes at 24 h post-DXR injection. n = 3 mice/group/point, per replicate, 4 replicates. * p< 0.05, one-way ANOVA. The control and DXR-only treatment groups adapted from [27].

Mentions: To determine whether Dexra protects against DXR-induced DNA damage, dsDNA breaks were quantified as the Olive Moment (OM) following neutral comet assay lysis and electrophoresis of ovarian cells isolated from 4 week-old (adolescent) female mice 0–24 hours post- in vivo treatment with vehicle control, 20 mg/kg DXR, or 20 mg/kg Dexra + 20 mg/kg DXR. As illustrated in Fig 1A, DXR induced a time-dependent increase in dsDNA breaks in granulosa cells, peaking at 1.8-times greater than control by 24 h. This increase was attenuated in Dexra:DXR treated mice to levels within 10% of control values in granulosa cells from ovaries removed at all tested time points through 24 h after injection with DXR (Fig 1A). Similarly, Dexra decreased the DXR-induced ~1.5x fold increase in dsDNA breaks in stromal/thecal-enriched cell fractions to levels within ~12% of control values through 24 h post-DXR injection (Fig 1B). Oocytes exhibited ~1.4x increase in the quantity of dsDNA breaks 24 h post-DXR injection when compared to the vehicle control (Fig 1C). Dexra pretreatment restrained dsDNA breaks in oocytes to those values found in controls. dsDNA breaks were quantified in oocytes only at 24 h time points, as our previous studies showed DXR-induced dsDNA breaks were not detected in oocytes before 12 hours [12]. These data demonstrate Dexra shielded the ovary from DXR-induced DNA damage in adolescent female mice throughout the entire acute insult period and across all ovarian cell types. Dexra-mediated inhibition of DNA damage lasted for 24 hours, well beyond the time of DXR blood clearance in human patients (15–30 minutes) [25], indicating Dexra has the potential to mitigate DXR-induced DNA damage until it is cleared from the circulation.


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 prevents DXR-induced dsDNA breaks in ovarian cells.Neutral comet assay was performed on the indicated cell types. Panel A quantifies dsDNA breaks in granulosa-enriched cell populations at time points from 0–24 h post-DXR injection. Panel B quantifies dsDNA breaks in stromal/thecal-enriched cell populations at time points from 0–24 h post-DXR injection. Panel C bar graph quantifies dsDNA breaks in oocytes at 24 h post-DXR injection. n = 3 mice/group/point, per replicate, 4 replicates. * p< 0.05, one-way ANOVA. 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.g001: Dexra prevents DXR-induced dsDNA breaks in ovarian cells.Neutral comet assay was performed on the indicated cell types. Panel A quantifies dsDNA breaks in granulosa-enriched cell populations at time points from 0–24 h post-DXR injection. Panel B quantifies dsDNA breaks in stromal/thecal-enriched cell populations at time points from 0–24 h post-DXR injection. Panel C bar graph quantifies dsDNA breaks in oocytes at 24 h post-DXR injection. n = 3 mice/group/point, per replicate, 4 replicates. * p< 0.05, one-way ANOVA. The control and DXR-only treatment groups adapted from [27].
Mentions: To determine whether Dexra protects against DXR-induced DNA damage, dsDNA breaks were quantified as the Olive Moment (OM) following neutral comet assay lysis and electrophoresis of ovarian cells isolated from 4 week-old (adolescent) female mice 0–24 hours post- in vivo treatment with vehicle control, 20 mg/kg DXR, or 20 mg/kg Dexra + 20 mg/kg DXR. As illustrated in Fig 1A, DXR induced a time-dependent increase in dsDNA breaks in granulosa cells, peaking at 1.8-times greater than control by 24 h. This increase was attenuated in Dexra:DXR treated mice to levels within 10% of control values in granulosa cells from ovaries removed at all tested time points through 24 h after injection with DXR (Fig 1A). Similarly, Dexra decreased the DXR-induced ~1.5x fold increase in dsDNA breaks in stromal/thecal-enriched cell fractions to levels within ~12% of control values through 24 h post-DXR injection (Fig 1B). Oocytes exhibited ~1.4x increase in the quantity of dsDNA breaks 24 h post-DXR injection when compared to the vehicle control (Fig 1C). Dexra pretreatment restrained dsDNA breaks in oocytes to those values found in controls. dsDNA breaks were quantified in oocytes only at 24 h time points, as our previous studies showed DXR-induced dsDNA breaks were not detected in oocytes before 12 hours [12]. These data demonstrate Dexra shielded the ovary from DXR-induced DNA damage in adolescent female mice throughout the entire acute insult period and across all ovarian cell types. Dexra-mediated inhibition of DNA damage lasted for 24 hours, well beyond the time of DXR blood clearance in human patients (15–30 minutes) [25], indicating Dexra has the potential to mitigate DXR-induced DNA damage until it is cleared from the circulation.

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