title: Dexrazoxane Diminishes Doxorubicin-Induced Acute Ovarian Damage and Preserves Ovarian Function and Fecundity in Mice.
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.
authors.affiliation: Department of Animal Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Jenna
authors.initials: J
authors.lastname: Kropp
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Elon C
authors.initials: EC
authors.lastname: Roti Roti
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Ashley
authors.initials: A
authors.lastname: Ringelstetter
authors.affiliation: Department of Animal Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Hasan
authors.initials: H
authors.lastname: Khatib
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin National Primate Research Center, Madison, Wisconsin 53715, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Abbott
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Sana M
authors.initials: SM
authors.lastname: Salih
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D064730:Dexrazoxane / Q000627:therapeutic use*; D004317:Doxorubicin / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005298:Fertility / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010053:Ovary / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D020011:Protective Agents / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D020011:Protective Agents; D064730:Dexrazoxane; D004317:Doxorubicin