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Immunosuppressant Drug Prevents Tobacco Induced Lung
Cancer in Mice BETHESDA, Md., April 1, 2007--Rapamycin, an FDA-approved drug normally
used to help prevent the body from rejecting organ and bone marrow
transplants and also used to coat cardiac stents, was highly effective in
preventing the development of tobacco-related lung tumors in mice. In a study
published in the April 1, 2007 issue of Clinical Cancer Research, researchers
at the National Cancer Institute (NCI), part of the National Institutes of
Health, found that mice that were administered rapamycin one week after
exposure to a very common tobacco-specific carcinogen showed a 90 percent
decrease in the number of tumors, a 74 percent decrease in tumor size, and
fewer abnormalities within their cancer cells. The scientists work also shows
that mTOR, a protein targeted by rapamycin, plays a critical role in the
early stages of development of certain lung tumors caused by tobacco
exposure.
We estimate that there will be over 160,000 deaths from lung cancer this year,
and 90 percent of those will be attributed to smoking. Quitting smoking
reduces lung cancer risk by about 50 percent, said NCI Director John E.
Niederhuber, M.D. By exploring methods of chemoprevention via agents such as
rapamycin, we may be able to further reduce lung cancer risk. Previous studies in mice have shown that nicotine and its metabolic
byproduct, known as NNK, stimulate the activity of two proteins, Akt and
mTOR, in normal cells that line the airways in the lungs. This activation
makes the cells pre-cancerous. In addition, clinical studies have shown that
Akt is activated in the majority of pre-cancerous lesions in smokers, and
that Akt activation predicts shorter survival for non-small cell lung cancer
patients, particularly for those in early stages or with small tumors. These
studies suggested that Akt and mTOR are important elements in the formation
and maintenance of tobacco-carcinogen induced lung tumors, and that targeting
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 Cancer Research. The critical
question is whether this approach would be safe and effective in smokers at
high risk to develop lung cancer. Given that rapamycin is relatively
inexpensive and FDA-approved for other indications, we are designing clinical
trials in humans to address these questions and hope to have these answers in
the near future. Further research is needed to determine whether doses of rapamycin that
achieve an anti-tumor effect in mice are similarly effective in humans, and
whether giving a dose that would be sufficient for an anti-tumor effect would
cause unacceptable levels of immune suppression or toxicity. For more information on Dr. Denniss research, go to http://ccr.cancer.gov/Staff/Staff.asp?profileid=5727 For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency for
conducting and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both common and rare
diseases. For more information about NIH and its programs, visit www.nih.gov. -------------------------------------------------------------------------------- |