Dexrazoxane Abrogates Acute Doxorubicin Toxicity in Marmoset Ovary1

Abstract

Preservation of ovarian function following chemotherapy for nonovarian cancers is a formidable challenge. For prepubescent girls, the only option to prevent chemotherapy damage to the ovary is ovarian tissue cryopreservation, an experimental procedure requiring invasive surgeries to harvest and reimplant tissue, which carries the risk of cancer reintroduction. Drugs that block the primary mechanism of chemotherapy insult, such as dexrazoxane (Dexra) in the context of anthracycline chemotherapy, provide a novel approach for ovarian protection and have the potential to overcome current limitations to oncofertility treatment. Dexra is a catalytic topoisomerase 2 inhibitor that protects the mouse ovary from acute doxorubicin (DXR) chemotherapy toxicity in vitro by preventing DXR-induced DNA damage and subsequent gammaH2AX activation. To translate acute DXR ovarian insult and Dexra protection from mouse to nonhuman primate, freshly obtained marmoset ovarian tissue was cultured in vitro and treated with vehicle or 20 μM Dexra 1 h prior to 50 nM DXR. Cultured ovarian tissue was harvested at 2, 4, or 24 h post-DXR treatment. Dexra prevented DXR-induced DNA double-strand breaks as quantified by the neutral comet assay. DXR treatment for 24 h increased gammaH2AX phosphorylation, specifically increasing the number of foci-positive granulosa cells in antral follicles, while Dexra pretreatment inhibited DXR-induced gammaH2AX phosphorylation foci formation. Additionally, Dexra pretreatment trended toward attenuating DXR-induced AKT1 phosphorylation and caspase-9 activation as assayed by Western blots of ovarian tissue lysates. The combined findings suggest Dexra prevents primary DXR-induced DNA damage, the subsequent cellular response to DNA damage, and may diminish early apoptotic signaling in marmoset ovarian tissue. This study provides initial translation of Dexra protection against acute ovarian DXR toxicity from mice to marmoset monkey tissue.

Multidrug resistance transporter-1 and breast cancer resistance protein protect against ovarian toxicity, and are essential in ovarian physiology

“…Even in countries with such access, the delay in oncologic care and perhaps the lack of counseling regarding fertility preservation options result in many girls and women having irreparable damage to their ovary. Recently, Salih et al reported that Dexra (dexarazoxane), an inhibitor of topoisomerase 2, protects the ovary from doxorubicin by preventing DNA damage [50]. However, currently no medications are approved by the Federal Drug Administration to provide undisputed protection to the ovary from gonadotoxic agents routinely used in chemotherapy.…”

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

“…In a proof-of-concept study using immortalized KK-15 mouse granulosa cells, we demonstrated that Dexra protects granulosa cells from DXR-induced DNA damage and cytotoxicity in vitro in a manner consistent with inhibiting TOPII DNA cleavage, rather than oxidative stress [ 23 ]. Furthermore, Dexra treatment of in vitro- cultured mouse and marmoset ovaries prior to DXR administration reduced the number of dsDNA breaks, and rescued primary granulosa cell viability [ 23 , 24 ]. The data demonstrated the potential for Dexra to be an effective ovoprotective agent against DXR toxicity by blocking the initial insult as well as subsequent cellular demise.…”

An ovarian bioreactor for in vitro culture of the whole bovine ovary: a preliminary report

“…Great strides have been made through in vitro culture of ovarian cells and tissue pieces/slices [ 32 , 35 , 36 ]. These culture methods have long been a very useful tool for studying reproductive functioning and toxicology.…”