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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 mice survivorship through 8 months of life.Plot represents the percentage of animals that survived as a function of days post-treatment through 8 months of age. At experiment initiation across all trials: n = 16 Ctl (vehicle control), 16 DXR, 21 Dexra1:DXR1 (1:1 mg ratio), 16 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 12 DexraC10 mice, where n represents the total number of animals that received DXR treatment. Survival by 8 months was: 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. The control and DXR-only treatment groups adapted from [27].
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pone.0142588.g008: Dexra pretreatment prevents DXR-induced decrease in mice survivorship through 8 months of life.Plot represents the percentage of animals that survived as a function of days post-treatment through 8 months of age. At experiment initiation across all trials: n = 16 Ctl (vehicle control), 16 DXR, 21 Dexra1:DXR1 (1:1 mg ratio), 16 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 12 DexraC10 mice, where n represents the total number of animals that received DXR treatment. Survival by 8 months was: 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. The control and DXR-only treatment groups adapted from [27].

Mentions: In human patients, DXR increases mortality due to cardiac toxicity, while Dexra administered at a 10:1 dose prior to DXR (Dexra10:DXR1) blocks DXR-related cardiotoxicity. Consistent with adverse systemic effects including cardiotoxicity, DXR reduced mouse survivorship to 25% at 30 days post initial breeding (2 months post-DXR injection, Fig 8). Survivorship continued to decline in DXR-treated mice, with a loss of 75% of DXR-treated animals by the end of the breeding trial (7 months post-DXR injection). Animals treated with DXR had a high rate of labor dystocia and often did not respond to palliative treatment (see Methods), leading to retained pups and peritonitis, contributing to morbidity. Both Dexra1:DXR1 and Dexra10:DXR1treatment groups exhibited no more than 20% survival loss over the entire course of the breeding trial (Fig 8). At 8 months of age, survivorship was 81% for Dexra1::DXR1, 88% for Dexra10:DXR1 and 87.5% for vehicle control animals (p<0.05 for all groups when compared to DXR-treated animals, Fig 8). While survivorship advantages have been reported for high doses of Dexra (Dexra10:DXR1), these data surprisingly demonstrate that low doses of Dexra (Dexra1:DXR1) may similarly provide protection from DXR-related mortality.


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 mice survivorship through 8 months of life.Plot represents the percentage of animals that survived as a function of days post-treatment through 8 months of age. At experiment initiation across all trials: n = 16 Ctl (vehicle control), 16 DXR, 21 Dexra1:DXR1 (1:1 mg ratio), 16 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 12 DexraC10 mice, where n represents the total number of animals that received DXR treatment. Survival by 8 months was: 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. 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.g008: Dexra pretreatment prevents DXR-induced decrease in mice survivorship through 8 months of life.Plot represents the percentage of animals that survived as a function of days post-treatment through 8 months of age. At experiment initiation across all trials: n = 16 Ctl (vehicle control), 16 DXR, 21 Dexra1:DXR1 (1:1 mg ratio), 16 Dexra10:DXR1 (10:1 mg ratio), 12 DexraC1, and 12 DexraC10 mice, where n represents the total number of animals that received DXR treatment. Survival by 8 months was: 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. The control and DXR-only treatment groups adapted from [27].
Mentions: In human patients, DXR increases mortality due to cardiac toxicity, while Dexra administered at a 10:1 dose prior to DXR (Dexra10:DXR1) blocks DXR-related cardiotoxicity. Consistent with adverse systemic effects including cardiotoxicity, DXR reduced mouse survivorship to 25% at 30 days post initial breeding (2 months post-DXR injection, Fig 8). Survivorship continued to decline in DXR-treated mice, with a loss of 75% of DXR-treated animals by the end of the breeding trial (7 months post-DXR injection). Animals treated with DXR had a high rate of labor dystocia and often did not respond to palliative treatment (see Methods), leading to retained pups and peritonitis, contributing to morbidity. Both Dexra1:DXR1 and Dexra10:DXR1treatment groups exhibited no more than 20% survival loss over the entire course of the breeding trial (Fig 8). At 8 months of age, survivorship was 81% for Dexra1::DXR1, 88% for Dexra10:DXR1 and 87.5% for vehicle control animals (p<0.05 for all groups when compared to DXR-treated animals, Fig 8). While survivorship advantages have been reported for high doses of Dexra (Dexra10:DXR1), these data surprisingly demonstrate that low doses of Dexra (Dexra1:DXR1) may similarly provide protection from DXR-related mortality.

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