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

(2011) AGING-US. 3(8). p.782-793
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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.
Keywords
FERTILITY PRESERVATION, CENTRAL-NERVOUS-SYSTEM, ATAXIA-TELANGIECTASIA, DEPENDENT APOPTOSIS, MITOTIC CATASTROPHE, CHILDHOOD-CANCER, ATM, DAMAGE, TISSUE, Chemotherapy, SENESCENCE, Aging, Fertility Preservation, Apoptosis, Double Strand DNA Breaks, Doxorubicin, Ovary

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Citation

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MLA
Soleimani, Reza et al. “Mechanisms of Chemotherapy-induced Human Ovarian Aging: Double Strand DNA Breaks and Microvascular Compromise.” AGING-US 3.8 (2011): 782–793. Print.
APA
Soleimani, R., Heytens, E., Darzynkiewicz, Z., & Oktay, K. (2011). Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. AGING-US, 3(8), 782–793.
Chicago author-date
Soleimani, Reza, Elke Heytens, Zbigniew Darzynkiewicz, and Kutluk Oktay. 2011. “Mechanisms of Chemotherapy-induced Human Ovarian Aging: Double Strand DNA Breaks and Microvascular Compromise.” Aging-us 3 (8): 782–793.
Chicago author-date (all authors)
Soleimani, Reza, Elke Heytens, Zbigniew Darzynkiewicz, and Kutluk Oktay. 2011. “Mechanisms of Chemotherapy-induced Human Ovarian Aging: Double Strand DNA Breaks and Microvascular Compromise.” Aging-us 3 (8): 782–793.
Vancouver
1.
Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. AGING-US. 2011;3(8):782–93.
IEEE
[1]
R. Soleimani, E. Heytens, Z. Darzynkiewicz, and K. Oktay, “Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise,” AGING-US, vol. 3, no. 8, pp. 782–793, 2011.
@article{6999464,
  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.},
  author       = {Soleimani, Reza and Heytens, Elke and Darzynkiewicz, Zbigniew and Oktay, Kutluk},
  issn         = {1945-4589},
  journal      = {AGING-US},
  keywords     = {FERTILITY PRESERVATION,CENTRAL-NERVOUS-SYSTEM,ATAXIA-TELANGIECTASIA,DEPENDENT APOPTOSIS,MITOTIC CATASTROPHE,CHILDHOOD-CANCER,ATM,DAMAGE,TISSUE,Chemotherapy,SENESCENCE,Aging,Fertility Preservation,Apoptosis,Double Strand DNA Breaks,Doxorubicin,Ovary},
  language     = {eng},
  number       = {8},
  pages        = {782--793},
  title        = {Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise},
  volume       = {3},
  year         = {2011},
}

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