Drug spares eggs from early death.

Current treatments can often stop cancer in its tracks, but only at great cost. By stimulating the process that leads to egg cell death, some therapies cause sterility and premature menopause. Now, for the first time, scientists have found a drug that prevents radiation therapy from triggering this process in mouse ovaries. If the substance works in people, it might lower the lifelong price that women pay for the benefits of cancer therapy.

When cancer treatments send a woman's egg cells down the path to early death, the surrounding estrogen-producing cells die as well. That leads to menopause in patients as young as 30 years old. The lack of estrogen exposes a woman to serious ailments including osteoporosis, cardiovascular disease, macular degeneration, and neurological disorders.

"So, what we set out to do is keep the ovaries [of cancer patients] functioning," says Jonathan L. Tilly of Massachusetts General Hospital in Boston. In the October NATURE MEDICINE, he and his colleagues describe their efforts toward this goal.

The team set off on the trail that led to their potentially egg-saving drug while examining the mechanism by which cancer treatments kill egg cells. They studied a mutant mouse strain lacking an enzyme called acid sphingomyelinase. The enzyme controls production of a cellular substance, ceramide, which triggers the natural process of egg cell death.

The scientists noticed that the enzyme-deficient eggs survived chomotherapy much better than normal mouse eggs did. So, they suspected that blocking ceramide might also protect the eggs from premature death.

To test their hunch, the scientists injected the ceramide inhibitor S1P into one ovary of each of a group of mice. Then, they irradiated these animals and untreated mice. The S1P-free ovaries lost 80 percent of their egg cells. However, the drug-treated ovaries retained as many egg cells as ovaries with no radiation exposure at all did.

"We were almost shocked that SIP worked as well as it did," Tilly says.

"Their data on the effects [of the inhibitor] are impressive," comments reproductive biologist Roger G. Gosden of McGill University in Montreal. He praised the new drug strategy for being less invasive than the egg-protection technique he pioneered. Gosden removes and freezes a cancer patient's ovarian tissue before radiation treatment, then reimplants it afterwards.

Now, Tilly's group has started to investigate whether S1P might protect not just mice but women undergoing radiation therapy. The team grafts fragments of women's ovaries, taken after hysterectomies, into mice genetically engineered to accept foreign tissue. Once the ovaries take root, the scientists will irradiate the mice to test whether S1P protects the transplanted egg cells.

"If it works, it could suggest [human] clinical trials in the future," Tilly says.

After their initial focus on preventing premature menopause, the researchers also began investigating the technique's potential to prolong fertility. Given that radiation treatment damages egg cell DNA, the condition of the eggs protected by S1P remains in question.

Tilly's team fertilized the S1P-protected mouse eggs and found more than 80 percent of the resulting embryos appeared normal. Still, healthy-looking, early-stage embryos might have hard-to-detect genetic defects that will show up years later, cautions Michael Bookman, an oncologist at Fox Chase Cancer Center in Philadelphia.

Anticipating these issues, Tilly's group has started mating the irradiated, S1P-treated mice to study the health and fertility of their offspring.

"The fertility aspect of this is the hot issue," Tilly says. "But there are many women who've [already] had children and who are worried about becoming old before their time."