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Immunosuppressant Drug Prevents Tobacco Induced Lung Cancer in Mice

these proteins and the cellular pathway that they are associated with may be a realistic tactic for lung cancer chemoprevention. Because the most promising inhibitors of this pathway target mTOR as opposed to Akt, the researchers focused on an FDA-approved inhibitor of mTOR, rapamycin.

Investigators performed several experiments in mice to examine the effects of mTOR inhibition on new tumor formation and on established tumors. Mice were exposed to NNK (a carcinogen only found in tobacco) through injection into the peritoneum (the area that contains the abdominal organs). Rapamycin, which targets mTOR, was administered either one or 26 weeks after NNK administration. The group that was given rapamycin at week one was used to test the drug as a preventative agent. The group that received treatment at week 26 was used to test the effect on established tumors. A once daily dose given five out of seven days a week, which was a standard used in previous studies, was compared to an every-other-day, or ‘qod, regimen. Comparisons revealed that rapamycin levels were better maintained with an every-other-day administration.

Importantly, the levels of rapamycin achieved in mice were comparable to those in humans. On the daily regimen, which began on week 26, tumor size, the rate of tumor proliferation, and mTOR activity were reduced, but the rate at which tumor cells multiplied was unchanged. When rapamycin was administered one week after NNK, the every-other-day regimen was well tolerated and produced the best results in terms of tumor cell multiplication (90 percent reduction), cell abnormalities (changes in appearance, shape, etc.), and size (74 percent decrease). This was correlated with decreased proliferation of tumor cells and inhibition of mTOR.

Our studies provide an exciting link between exposure to an important tobacco carcinogen, NNK, and mTOR, said Phillip A. Dennis, M.D., Ph.D., head, Signal Transduction Section of NCI's Center for Cance
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