KYOTO, JAPAN Prophylactic oral N-acetylcysteine has shown early promise as a novel melanoma chemoprevention strategy, said Dr. Douglas Grossman.
Taking N-acetylcysteine (NAC) episodically in anticipation of a day at the beach or before other heavy sun exposure may prevent UV-induced oxidative damage to melanocytic nevi, thereby reducing the long-term risk of malignant transformation, explained Dr. Grossman at an international investigative dermatology meeting.
The drug targets oxidative damage, a specific oncogenic pathway that is induced by UV irradiation. NAC has the ability to sidestep the inherent drawbacks of daily chemopreventive therapy, including compliance problems and drug side effects, said Dr. Grossman of the University of Utah, Salt Lake City. And sunscreens alone seem inadequate for melanoma prevention; in fact, some studies have shown a higher incidence of melanoma in sunscreen users, he said.
NAC is an ideal drug to study for chemoprevention. It has a relatively short serum half-life of 5.5 hours. It is rapidly metabolized to cysteine and converted to glutathione, a potent antioxidant that is depleted by UV.
"NAC is well characterized, cheap, cell-permeable, and has a safety record already demonstrated in humans," the dermatologist noted.
Other investigators have already shown that NAC is useful in preventing oxidative damage in the skin. It is FDA approved for the treatment of toxicity from acute acetaminophen overdose. More recently, it has been used to prevent intravenous contrast-induced nephropathy.
In mouse studies, Dr. Grossman and coworkers have demonstrated that NAC prevents UV-induced formation of the carcinogen 8-oxoguanine and delays onset of UV-induced melanoma (Clin. Cancer Res. 2007;13:5952-8).
In Kyoto, he presented the first clinical study of NAC for melanoma chemoprevention. It involved eight patients who underwent biopsy of a nevus prior to administration of a single 1,200-mg oral dose of NAC. Three hours after NAC administration, a second nevus was removed. The nevi were then irradiated ex vivo with UV at 4,000 J/m
When the nevi were analyzed 24 hours post UV exposure, the control samples showed roughly a 50% reduction in glutathione levels and an increase in 8-oxoguanine, compared with baseline. In contrast, the nevi exposed in vivo to NAC showed no depletion of glutathione and no rise in 8-oxoguanine in three of eight patients.
In hindsight, Dr. Grossman said, the analysis probably should have been done 48 hours post UV exposure rather than at 24 hours. The earlier mouse studies suggested oxidative stress and damage were at their maximum levels at the 48-hour time point.
"We see this as a pilot study in which we had some moderate success in a small number of patients. We're now poised to do a second trial using the 48-hour time point, which we think will be much more robust," Dr. Grossman said at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.
Also planned are clinical trials looking at NAC's protective effect in response to UV irradiation in vivo. The possibility that NAC is protective when taken following UV exposure is also worthy of investigation, he added.
The optimal dose of NAC for chemoprevention remains unknown. The 1,200-mg dose used in this study was well tolerated. "Higher doses are probably safe, but we don't know if they'd confer greater protection or not, so we'll probably stick with 1,200 mg," said Dr. Grossman.
His study was funded by the university's Huntsman Cancer Institute.