Drug Preserves Ovarian Function in Mice

Embargoed: October 1, 2000; 5:00 pm EDT

Drug Shown to Preserve Ovarian Function in Mice

NEW YORK, October 1, 2000 -- For the first time, scientists have found a way to protect ovaries from the damage often caused by radiation and chemotherapy treatments for cancer. Researchers at Memorial Sloan-Kettering Cancer Center, along with colleagues from Massachusetts General Hospital and other institutions, have discovered that "knocking out" a particular gene protects the ovaries of mice from damage. Furthermore, knowledge of this genetic defect has led to a drug that -- when injected into mouse ovaries before radiation treatments -- preserves the ovaries' normal function, thus allowing them to continue producing eggs.

Early menopause and sterility are common side effects for women who undergo many types of cancer therapy. Cells in the ovary are particularly sensitive to cancer-treatment agents that induce a cell death mode known as apoptosis, or programmed cell death. In a study published in the October issue of Nature Medicine, researchers built upon knowledge of the cell-signaling pathway that leads to apoptosis and found a way to block it in ovarian cells.

"We have extended our research from a mechanistic understanding of the process of cell death to a pharmacologic intervention to affect that process," said Richard Kolesnick, M.D., head of the Signal Transduction Laboratory at Memorial Sloan-Kettering. Scientists are hopeful that further research eventually will lead to a drug treatment that could protect fertility in women who undergo cancer treatment.

In previous studies, Dr. Kolesnick and his colleague Zvi Fuks, M.D., Deputy Physician-in-Chief for Planning and head of the Metastatic Cell Biology Laboratory at Sloan-Kettering, have shown that apoptosis in some cell types begins when a cell membrane lipid called sphingomyelin is converted into another lipid, ceramide, leading to a chain reaction that prompts cells to commit suicide. Both radiation and chemotherapy induce this type of death by activating an enzyme termed sphingomyelinase in many types of cells, but its role in apoptosis of ovarian cells had not been shown until now.

In normal mammalian development, female embryos have many more eggs than they need, and about 80 percent of them die before birth. In the current experiments, researchers discovered that genetically engineered female mice that had the acid sphingomyelinase gene knocked out were born with many more eggs than normal mice. Further studies showed that the ovarian cells from these knockout mice were resistant to the effects of radiation and chemotherapy. The researchers knew the knockout mouse lacked the ceramide pathway, which indicated that the process of cell death in the normal mouse ovaries involved ceramide.

"We knew that if we could find a way to block this pathway and stop cell death, we could avoid a very serious side effect for women who undergo cancer treatment," explained Dr. Fuks.

A compound called sphingosine-1-phosphate (S1P) -- shown recently to block the sphingomyelin-ceramide pathway -- turned out to be just the ticket. The researchers treated normal mice with S1P, injecting the drug into one ovary and using the other ovary as a control. After the mice were given a radiation dose, their ovaries were examined, and the organs treated with S1P were found to retain normal appearance and function, whereas the untreated ovaries were shrunken and damaged.

The researchers then treated mice with S1P in both ovaries and exposed them to radiation. When eggs from the S1P-treated, irradiated mice were fertilized in vitro, the quality of the blastocysts (the stage of fertilized egg just prior to implantation) was much higher and the quantity was much greater than those of the untreated, irradiated mice. Thus, in addition to providing hope for women undergoing cancer treatment, the research has potential for improving assisted reproductive technologies such as in vitro fertilization. However, further research needs to be done in animals before tests using S1P in human patients can begin.

This collaborative research effort involved scientists from two different departments within MSKCC and at Massachusetts General Hospital, Mt. Sinai School of Medicine, and the Burnham Institute.

"This is a good example of a multidisciplinary approach to a problem," said Dr. Kolesnick. "It shows how genetics and biochemistry can be used successfully to define the mechanisms of how therapies work and -- by using that information effectively -- we can generate a pharmacological approach."

This research was supported by grants from the National Institutes of Health and Vincent Memorial Research Funds.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its distinguished history, the Center has played a leadership role in defining the standard of care for patients with cancer.

# # #