Cream Prevents Sun Damage In Red-Haired Mice

BOSTON, Sept. 20 -- Now when Mickey and Minnie Mouse go to the beach in Florida, they'll be able to avoid sunburn and lower the risk of squamous-cell carcinoma by rubbing on a compound that mimics natural tanning.

Researchers here took red-furred mice -- who have the same genetic difference that in humans leads to pale skin and red hair -- and genetically modified them so their skin contained melanin-producing cells.

Much as fair-skinned, redheaded humans have limited tanning ability, the modified mice could not tan. But an application of a cream containing the compound forskolin increased melanin levels in their skin and created a sunless suntan, according to David Fisher, M.D., Ph.D., of the Dana-Farber Cancer Institute here, and colleagues.

When treated mice were exposed to ultraviolet light, they experienced less sun damage than control mice, Dr. Fisher said in an interview.

The experiments suggest both a new paradigm of how tanning occurs and a possible way humans might reduce their risk, Dr. Fisher and colleagues reported in the Sept. 21 issue of Nature.

The forskolin compound used in the study has not yet been tested in humans for tanning, but Dr. Fisher said that the results "demonstrate the principle that actual tanning can be 'rescued' by recognizing the normal pathway and the precise step where it is blocked in people who do not tan well."

People who naturally tan well are at lower risk for skin cancer, so a medicinally induced tan might lower the risk for those with fair skin, the researchers said.

People who naturally tan well are at lower risk for skin cancer, so a medicinally induced tan might lower the risk for those with fair skin, Dr. Fisher said.

But he said more research is needed before the sunless suntan is ready for the market. First, he said, scientists need to clearly understand exactly what's happening biochemically.

Next, the compound used to produce the suntan needs to be optimized. Mouse skin is thinner than human and differs in other ways as well, he said, so that forskolin might not work as well in people an in the animals.

Luckily, he said, there is "huge range" of similar compounds available. "Forskolin was just the first one we tried," he said.

And finally, Dr. Fisher said, the safety of the approach must be confirmed. A topical compound usually limits systemic exposure to active substances, but "you never know and you need to test."

The current paradigm of tanning is that the increase in melanin is a response by melanocytes to damage by ultraviolet light, but Dr. Fisher and colleagues now believe the process begins with keratinocytes.

Ultraviolet light stimulates these cells to produce melanocyte stimulating hormone, which homes to a receptor on the melanocytes. The melanocytes then release cyclic adenosine monophosphate (cAMP), which in turn stimulates the production of melanin.

In people with pale skin and red hair, the receptor for melanocyte stimulating hormone is malformed, the researchers believe, so that cAMP levels remain low and red/blond melanin is formed, instead of the more protective brown/black melanin.

To verify the theory, Dr. Fisher and colleagues engineered mice with an analogous melanocyte stimulating hormone receptor to that found in red-headed humans and produced a breed of red-haired mice whose skin contained melanocytes but which sunburned instead of tanning.

"These animals couldn't tan," Dr. Fisher said. "We'd proven in a rigorous genetic system what people have known for hundreds of years: Redheads don't tan well."

But when the animals were treated with forskolin - which increases cAMP levels -- they turned dark, demonstrating that the defective melanocyte stimulating hormone receptor did not permanently prevent the production of melanin.

What's more, the sunless suntan appears almost identical to that seen in dark-haired mice that tan naturally, the researchers reported.

"When keratinocytes absorb melanin pigment, the pigment isn't randomly distributed within them," Dr. Fisher said. "It forms arcs that look like tiny umbrellas over the keratinocyte's nucleus. When we artificially caused our red-haired mice to tan, the pigment in their keratinocytes made the exact same umbrella-like pattern."

The researchers crossed the red-haired mice with mice known for their propensity to develop cancer and treated them with either forskolin or a control cream for four weeks before exposing them to ultraviolet light.

The exposure -- over a 20-week period -- was the equivalent of about one or two hours of midday sun at sea level in Florida during July.

The control mice exhibited gross and histologic evidence of sun damage, including failure to thrive, profound epidermal thickening, and inflammation and scarring, but the forskolin mice had significantly less damage, the researchers said.

Eleven neoplasms - most of them squamous cell carcinoma -- developed in the nine control mice within nine weeks after the ultraviolet exposure was stopped.

The treated mice developed six tumors but the onset was dramatically delayed: a median of four weeks for the control animals and 25 weeks for the treated mice, a difference that was significant at P<0.001.

"We were amazed at how much of a delay there was," he said.

Dr. Fisher added that emerging data suggest that sunscreens may not have a large protective effect against melanoma. In that case, he said, a medicinally induced suntan might move some people from having a high-risk for melanoma into the group with low risk.