How do chemotherapeutic agents damage the ovary?
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Morgan2014.doc (39.38Mb)
Date
28/06/2014Author
Morgan, Stephanie
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Abstract
Chemotherapy treatment in premenopausal women has been linked to premature
ovarian failure (POF), and hence infertility, through ovarian follicle loss. The exact
mechanisms that lie behind this loss are unclear and so the action of two commonly
used chemotherapeutic agents were compared here. Cisplatin is a DNA cross-linking
agent commonly used in the treatment of ovarian, lung and bladder cancers, while
the anthracycline doxorubicin is commonly used to treat leukaemia and breast
cancer. Neonatal mouse ovaries were cultured in vitro and exposed to cisplatin or
doxorubicin in order to determine their effects on primordial and early growing
follicles. Both drugs caused a dose dependant follicle loss but targeted different cell
types. Cisplatin caused a significant increase in follicles with unhealthy oocytes;
furthermore primary stage follicles were the follicle class most affected (up to 98%
classified as unhealthy compared with 13% in control, p<0.001). In contrast,
doxorubicin caused a significant increase in follicles with unhealthy granulosa cells
and affected all follicle stages present. When the mechanism of cell death was further
investigated, apoptosis was the main pathway through which these drugs cause
ovarian cell death. Doxorubicin in particular caused a significant increase in
apoptosis of ovarian somatic cells including the granulosa cells and stroma. Imatinib
mesylate, a tyrosine kinase inhibitor which is also used as a chemotherapeutic agent,
has been implicated as a potential therapy to block the ovotoxic effects of cisplatin.
Results here confirm this finding (29% of follicles classified as unhealthy in the
cisplatin only group compared to 8% in the cisplatin and imatinib co-treatment
group, p<0.001) and found further, that imatinib was unable to protect against
doxorubicin-induced damage (28% of follicles classified as unhealthy in the
doxorubicin treated group compared to 19% in the doxorubicin and imatinib cotreatment
group). Imatinib treatment alone in newborn ovaries caused a significant
increase in the number of follicles present at the end of culture compared to control
(402±43 in the imatinib group compared to 188±34 in control, p<0.001), which is
likely due to an effect on follicle formation. In conclusion, the work presented in this
thesis demonstrates drug specific actions of cisplatin and doxorubicin on the mouse
ovary. This suggests that any therapy designed to confer ovarian protection in the
future may have to be tailored to be drug specific.