Abstract
Increasing numbers of female patients survive cancer, but succumb to primary ovarian insufficiency after chemotherapy. We tested the hypothesis that Bortezomib (Bort) protects ovaries from doxorubicin (DXR) chemotherapy by treating female mice with Bort 1 hour prior to DXR. By preventing DXR accumulation in the ovary, Bort attenuated DXR-induced DNA damage in all ovarian cell types, subsequent γH2AFX phosphorylation, and resulting apoptosis in preantral follicles. Bort pretreatment extended the number of litters per mouse, improved litter size and increased pup weight following DXR treatment, thus increasing the duration of post-chemotherapy fertility and improving pup health. As a promising prophylactic ovoprotective agent, Bort does not interfere with cancer treatment, and is currently used as a chemotherapy adjuvant. Bort-based chemoprotection may preserve ovarian function in a non-invasive manner that avoids surgical ovarian preservation, thus diminishing the health complications of premature menopause following cancer treatment.
Highlights
Improvements in cancer detection and treatment have dramatically increased post-cancer life expectancy
Promising animal and in vitro studies have identified potential fertoprotective agents including FTY720, dexrazoxane, AS101, sphingosine-1-phosphate, imatinib, tamoxifen, and goserelin, [7,8,9,10,11,12,13], but none have yet been implemented in clinical practice
Oocytes were not examined for DNA damage at earlier time points, as we previously demonstrated absence of DXR-induced DNA damage until at least 10 hrs postinjection
Summary
Improvements in cancer detection and treatment have dramatically increased post-cancer life expectancy. Premature menopause resulting from POI causes infertility and increases a woman’s risk of complications from estrogen deficiency, including osteoporosis, mental health disorders, and cardiovascular disease. While re-transplanted tissue provides transient return of menstrual hormone cycles, it is an expensive, invasive, experimental procedure that risks reintroducing the original cancer back into the patient at the time of re-transplantation [2,5]. Oocyte and embryo cryopreservation are established procedures for women, but require expensive treatments that delay cancer therapy and do not preserve estrogen production [6]. A drug-based ovarian shield (ovoprotective agent) administered as a prophylactic has potential to prevent ovarian chemo toxicity, and maintain reproductive health, including endocrine function and fertility, for all pre-menopausal cancer survivors regardless of cancer type
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