Kill the cancer, save the eggs. (Reproductive Health).

When young women are diagnosed with cancer and undergo radiation or chemotherapy to save their lives, they must contend with the devastating knowledge that the anticancer therapy could leave them infertile. Now researchers say their experiments with animal models suggest that a pharmaceutical agent could preserve the integrity of these patients' ovaries, allowing them to continue developing viable eggs.

"At radiation doses that sterilize ninety-five percent of mice, we were able to protect virtually all the female mouse eggs with the natural compound sphingosine 1-phosphate," says Richard Kolesnick, head of the Laboratory of Signal Transduction at Memorial Sloan-Kettering Cancer Center in New York City and principal investigator of the study, reported in a letter in the September 2002 issue of Nature Medicine. Not only were the eggs protected, but Kolesnick says that two generations of offspring produced by the protected females appeared normal by numerous biologic and genetic criteria.

"Right now there is no proven therapy that will preserve fertility in women undergoing radiotherapy or chemotherapy," says Kolesnick. "What this research suggests is that, when using a sphingosine 1-phosphate-based pharmaceutical approach, it might be possible to one day preserve ovarian function without propagating genetic damage."

"Nothing to date has provided protection," says Sanford Rosenberg, cofounder of the Richmond (Virginia) Center for Fertility and Endocrinology. He says attempts to preserve fertility by freezing ovarian tissue remains experimental. With the help of fertility specialists, some couples create embryos prior to chemotherapy that can be implanted at a later date after successful cancer treatment. Rosenberg says any development that could preserve fertility in women would be welcomed.

Kolesnick and his team observed that ceramide, a natural lipid, controls the apoptosis--programmed cell death--of eggs. Although scientists currently believe that egg loss after anticancer therapy occurs to preserve the integrity of the genome, he says, recent research suggests that the ceramide cascade works to eliminate eggs based on activation of membrane-based signaling pathways independent of DNA damage. So there may in fact be some other reason for the loss of the eggs. Sphingosine 1-phosphate, which is a metabolite of ceramide, functions to prevent initiation of the apoptotic cycle, and preserves eggs without evidence of DNA damage.

The researchers injected 8 female mice with the compound and then exposed them to radiation. Another group of 8 mice were injected with a placebo and also irradiated. In the first mating trial after these procedures, 50% of the mice given the placebo produced litters, compared with all of the mice given sphingosine 1-phosphate. By the fourth mating trial, just 1 mouse not protected by sphingosine 1-phosphate was able to bear a litter, compared with 6 of the protected mice.

"This kind of approach to solving such a problem goes beyond the expertise of one single group," Kolesnick says, noting that the study required input from physicians, radiation oncologists, biochemists, and fertility, genomics, and genetics experts. Four institutions were involved in the project.

"While this approach holds promise, there is a lot more research that needs to be performed," Kolesnick says. "[But] we think we have established proof in principle that we can accomplish the protection of the [eggs] safely."