For Nicotine, Dose Matters
Because several preclinical studies had shown that nicotine itself can be a tumor promoter, researchers wanted to find out whether or not longer term NRT is a safe option for smokers who are trying to quit.
Nicotine replacement therapy (NRT) is frequently part of a person’s regimen for smoking cessation. The U.S. Food and Drug Administration has approved use of this approach for 12 weeks in supervised quitting programs. Unfortunately for some patients, though, this length of time is not long enough to break their addiction to tobacco.
Because several preclinical studies had shown that nicotine itself can be a tumor promoter, CCR researcher Colleen Maier, working with Phil Dennis, M.D., Ph.D., in the Signal Transduction Section of the Medical Oncology Branch, wanted to find out whether or not longer term NRT is a safe option for smokers who are trying to quit.
Noting that in many of the preclinical studies, nicotine was administered at doses that are unachievable in humans, the Dennis team adjusted the doses downward and tested lower--humanly relevant--nicotine levels in three different mouse models of lung tumorigenesis. They reported their findings recently in Cancer Prevention Research.
The Dennis team chose three different mouse models of lung tumorigenesis driven by mutant K-Ras because these mutations are common features of lung cancers in smokers. They administered nicotine in the drinking water to achieve steady-state levels that are commonly observed in former smokers who undergo NRT. In a carcinogen-driven model, a transgenic mutant K-Ras model, and a syngeneic xenograft model, nicotine did not increase lung tumors—not in cell number, size, or rate of metastasis. In addition, nicotine did not shorten the survival of mice who already had lung tumors. In fact, even the signaling pathways that are commonly activated by nicotine in vitro were not activated in tumors in mice after nicotine was absorbed from the drinking water. Yet when higher unphysiologic doses were used, nicotine did increase activation of signaling pathways in vitro.
Overall, using mouse models of lung cancer, Dennis and his team found that nicotine does not promote mutant K-Ras-driven lung tumorigenesis when used at concentration levels that are similar to those measured in the blood of smokers receiving NRT.
If this data from animal models of lung cancer is relevant to absorption rates in humans, it appears that extending the length of time smokers undergo NRT should not increase their risk of promoting their own lung cancer.
Maier, C.R., Hollander, M.C., Hobbs, E.A., Dogan, I. and Dennis, P.A. Nicotine does not enhance tumorigenesis in mutant K-Ras-driven mouse models of lung cancer. OnlineFirst October 25, 2011; doi: 10.1158/1940-6207.CAPR-11-0365 Reviewed by Donna Kerrigan