Oct. 3, 2000 Study may lead to ways to preserve fertility in women undergoing cancer treatment
A team of researchers from the Massachusetts General Hospital (MGH), Memorial Sloan-Kettering Cancer Center in New York, and other research centers has found a molecule that, in animal studies, has blocked the destruction of ovarian egg cells (oocytes) by radiation therapy. The report in the October issue of Nature Medicine describes how a compound called sphingosine-1-phosphate (S1P), which blocks the activity of a cell-death-associated molecule called ceremide, preserved ovarian egg cells and fertility in female mice exposed to levels of radiotherapy that otherwise would have destroyed their ovaries. The researchers expect that the same protection would be afforded to ovaries exposed to chemotherapeutic drugs.
"For the first time we have a promising prospect for a small molecule that could be given to women and girls undergoing cancer treatment to protect their ovaries," says Jonathan Tilly, PhD, the paper's senior author. However, he notes that further research needs to be completed before trials of S1P could be attempted in human patients.
All mammalian females are born with a huge supply of immature egg cells that is depleted throughout their lives by a process called programmed cell death or apoptosis. Only a tiny fraction of the oocytes a female is born with actually mature and are released from the ovaries as eggs. It has long been known that treatment with chemotherapy drugs and radiation therapy can accellerate the death of oocytes, resulting in premature menopause and infertility among many women and young girls who are treated for cancer.
In previous research, Tilly's team at the MGH Vincent Center for Reproductive Biology had shown that oocytes were destroyed by chemotherapy through a particular cell-death pathway involving the interaction of three principal signs called ceramide, Bax and caspase-2. They also showed that knocking out the genes either for Bax or caspase-2 prevented normal oocytes loss in female mice.
The current study focuses on the earliest stages of the ceramide-Bax-caspase pathway, which begins when a lipid molecule called sphingomyelin is converted into ceramide by an enzyme called sphingomyelinase (SMPD-1). The MGH team joined forces with researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) who previously had shown that conversion of sphingomyelin to ceramide sets off the death of several types of cells in response to chemotherapy or radiation therapy. That event's role in the death of oocytes, however, had not previously been shown.
Experiments conducted by Yutaka Morita, MD, PhD, and Gloria Perez, DVM, PhD, of the MGH first confirmed the role of sphingomyelin in oocyte death by showing that mice lacking the SMPD-1 gene, similar to those in the previous studies of bax or caspase-2 knockout mice, did not experience normal oocyte depletion. Other tests showed that oocytes from SMPD-1-knockout mice were resistant to cell death caused by the cancer drug doxorubicin and that treating normal ovarian cells with S1P, which is known to block the sphingomyelin cell-death pathway, provided similar protection.
Based on these results, the researchers devised experiments to test whether blocking the sphingomyelin pathway could actually protect oocytes from death in living animals. Prior to exposing a group of normal female mice to a dose of radiation that would be expected to destroy most of their oocytes, the researchers injected S1P into the sac surrounding one ovary in each mouse. Two weeks later, the ovaries receiving S1P appeared healthy, with a quantity of normal-appearing follicles - the tiny sacs in which egg cells grow - that was similar to that seen in non-irradiated mice, while the unprotected ovaries showed almost complete destruction of follicles. Mice receiving the highest doses of S1P showed the greatest level of protection in the radiation-treated ovaries.
The researchers then collected oocytes from female mice that had been irradiated after receiving injections containing either S1P or an inert liquid, fertilized them with sperm from male mice, and allowed the fertilized cells to develop to the blastocyst stage, which immediately precedes implantation. Although cells from both groups of mice were fertilized at similar rates, significantly more of those from the mice who had received S1P developed normally into healthy-appearing blastocysts.
"We targeted sphingomyelin and S1P in this study because they work at the very earliest steps of the cell-death process," Tilly explains. "From a biological standpoint, the earlier we can head off cell death signalling, the healthier the cell will be. We're very gratified to see this theory supported in living animals."
Tilly adds that the next step will be to see whether S1P provides similar protection to human ovarian tissue that has been implanted into mice. Providing evidence that S1P actually protects human ovaries would strongly justify any potential testing of the technique in human volunteers.
The Memorial Sloan-Kettering (MSKCC) group was led by Richard Kolesnick MD, of the Laboratory of Signal Transduction and Zvi Fuchs, MD, of the Department of Radiation Oncology. Other co-authors of the Nature Medicine paper are Francois Paris, PhD, Desiree Ehleiter and Adrianna Haimovitz-Friedman, PhD, at MSKCC; Silvia Miranda and Edward Schuchman, PhD, of Mt. Sinai School of Medicine in New York; and Zhihua Xie, PhD, and John Reed, MD, PhD, of the Burnham Institute, La Jolla Calif. The study was supported by grants from the National Institutes of Health, Vincent Memorial Research Funds, the Japanese Society for the Promotion of Science, and the Harvard Center of Excellence in Women's Health.
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