SAN FRANCISCO–Researchers have found the molecular pathway that can prevent the death of immature ovarian eggs in female mice, potentially preserving their fertility and endocrine function by adding a currently approved drug, imatinib mesylate, to the other chemotherapy drug cisplatin. The results were presented Monday at The Endocrine Society’s 95th Annual Meeting in San Francisco.
“Young women who receive cancer treatment often lose their fertility,” said the study’s principal investigator, So-Youn Kim, PhD, a postdoctoral fellow in the laboratory of Teresa Woodruff, PhD, at Northwestern University in Chicago. “Our research is one more step in finding a medical treatment to protect the fertility and hormone health of girls and young women during cancer treatment.”
Radiation or chemotherapy with drugs such as cisplatin can permanently damage and kill a woman’s immature eggs, or oocytes, in ovarian follicles (sacs in the ovaries that contain the oocytes), which, unlike hair follicles, do not self-renew, Kim said.
Prior research has suggested that imatinib (trade name Gleevec) is a fertility-protecting drug against cisplatin, but reports of the drug’s effectiveness have been contradictory, Kim said. Imatinib is a type of drug called a tyrosine kinase inhibitor, which prevents substrate binding and blocks induction of the signal that tells a tumor cell to grow and divide. It is approved for treatment of certain types of leukemia like Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
To confirm that imatinib protects oocytes against cisplain, the researchers cultured ovaries from 5-day-old mice with treatment of cisplatin and imatinib for 96 hours in vitro and also used a kidney grafting method to monitor long-term effects.
The molecular signaling pathway by which oocytes die after chemotherapy or radiation treatment is not well understood, according to Kim. In this study, funded by the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, she and her co-workers investigated the role of a molecule called TAp63, which is expressed in the oocyte nucleus during follicle development and is known to be essential for radiation-induced oocyte death, as well as p63 family members, p53 and p73.
In “conditional knockout” mice that lacked the p63 gene specifically in the oocytes, they found that cisplatin administration did not induce apoptosis, or programmed cell death. Thus, the numbers of immature ovarian follicles compared with those in normal control mice was not affected.
This finding means that “TAp63 is essential for apoptosis of oocytes” exposed to cisplatin, Kim said.
Although imatinib did not block cisplatin-induced DNA damage, it did inhibit apoptosis, permitting time for the oocytes to recover, Kim said.
“Our research has identified the potential target molecules in the prevention of oocyte death,” she said. “If we are successful [in blocking the effects of chemotherapeutics on the ovarian follicle], oocytes from young female cancer patients will be protected by their treatments and endocrine function can be maintained.”
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