Research Article: Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise

Date Published: August 22, 2011

Publisher: Impact Journals LLC

Author(s): Reza Soleimani, Elke Heytens, Zbigniew Darzynkiewicz, Kutluk Oktay.

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Abstract

The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors.

Partial Text

Chemotherapy-induced ovarian failure not only increases the risk for early menopause-related complications but also results in infertility in young female cancer survivors [1, 2]. In general, underlying mechanisms of this chemotherapy-induced ovarian aging is inadequately characterized in humans.

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the New York Medical College (NYMC) Institutional Animal Care and Use Committee. The study protocol was approved by the institutional review board of NYMC and written informed consent was obtained from all participants involved in the study. All surgery was performed under anesthesia, and all efforts were made to minimize suffering. Ovarian tissue fragments were obtained from consenting females patients, or their parents in the case of minors, (n=6, age range 2-37) during ovarian tissue cryopreservation procedures before chemotherapy.

Doxorubicin is a key chemotherapeutic agent used in the treatment of numerous malignancies such as breast, ovarian, and endometrial cancers as well as lymphomas, acute leukemias, and many others which are commonly encountered during the premenopausal ages [16, 17, 18, 19]. In the present study we investigated the mechanism of chemotherapy-induced ovarian aging induced by this drug in vitro and in vivo on human and mice ovaries.

This study was supported by the National Institute of Child Health and Development as well as National Cancer Institute, National Institute of Health (HD 053112 and R21HD061259) to KO. In addition, ZD is supported by RO1 NCI 28 704.

 

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