Lung cancer is the most common and deadly
malignancy in the United States and throughout the world. It is the
leading cancer killer of both men and women in the United States, and
is expected to be responsible for approximately 31% of all cancer
deaths in men and 25% of cancer deaths in women in 1999. Overall, the
5-year survival rate for lung cancer is only 15%.
Since 90% of lung cancers are tobacco related, primary prevention of
lung cancer by smoking prevention and cessation is one of the highest
priorities for United States health policy. In the United States
today, 50 million individuals are current smokers, and another 50
million are former smokers. In fact, 50% of newly diagnosed lung
cancers occur in former smokers, perhaps due to persistent genetic
changes in the bronchial epithelium from tobacco carcinogens.[2,3]
Chemoprevention is defined as the use of specific natural or
pharmacologic agents to reverse, suppress, or prevent the
carcinogenic process to the development of invasive cancer.
The basic idea behind lung cancer chemoprevention is the concept that
diffuse injury of the respiratory epithelium results from chronic
carcinogen exposure. This is known as field cancerization,
which describes the diffuse mucosal changes observed in patients
with head and neck cancers. These changes, identified from resected
surgical specimens of carcinoma of the oral cavity, were of three
primary histologic abnormalities surrounding the primary tumor:
Hyperplasia (an increase in the number of rows in the epithelium),
hyperkeratinization, and dyskariosis (atypia). When the entire
surgical specimen was further sectioned, separate foci of in situ and
invasive carcinoma were frequent findings. Basically, the entire
upper aerodigestive tract is exposed to long-term carcinogenic insult
(in this instance, cigarette smoke), and is therefore at increased
risk of developing cancer.[1-4]
The evidence for multistep carcinogenesis in this setting also
includes genetic damage to lung tissue, demonstrated by the linear
relationship between genetic instability (eg, polysomy of chromosomes
3, 9, and 17) in human lung tissue and cigarette smoking, and the
increased frequency of proliferative markers in high-risk tissues and
premalignant lesions (Figure 1).[5-9]
Auerbach et al sectioned the entire tracheobronchial trees of chronic
smokers and patients who died of lung cancer. They recorded three
major types of epithelial changes: an increase in the number of cell
rows, loss of cilia, and the presence of atypical cells. The most
striking finding was the frequency of carcinoma in situ, a lesion
composed entirely of atypical cells without cilia in an average
thickness of 5 or more cell rows; this finding was observed in 15% of
the sections from those who died of lung cancer. These lesions were
found in 4.3% of sections from men who smoked one to two packs of
cigarettes per day, and 11.4% of sections from those who smoked two
or more packs per day.[5,6,10,11] These lesions were never found in
pathologic specimens of nonsmokers, and few were found in the
bronchial trees of light smokers.
The field of chemoprevention grew in large part out of the
epidemiologic data demonstrating the existence of dietary inhibitors
of carcinogenesis. The rationale for chemoprevention arose from a
combination of sources: epidemiologic data demonstrating the
existence of dietary inhibitors of carcinogenesis, basic studies of
epithelial carcinogenesis, and laboratory evidence from animal
models.[5,12-15] Despite these data, difficulty has persisted in
determining which specific compounds within complex foods provide
anticarcinogenic (or carcinogenic) effects.
The term chemoprevention was coined by Michael B. Sporn
to define the use of specific natural or synthetic chemical agents to
reverse, suppress, or prevent carcinogenic progression to invasive
cancer.[3,4] In 1981, Peto et al examined the impact of dietary
b-carotene on the reduction of human cancer rates. Several groups had
previously demonstrated an inverse correlation between human cancer
risk, blood retinol, and dietary b-carotene.
They reviewed the literature on whether supplemental b-carotene
or vitamin A could materially retard the carcinogenic process. The
cancer-preventive data from epidemiologic studies led to in vitro and
in vivo (animal) laboratory studies evaluating the specific
components of complex foods. Whereas these studies discovered many
agents with laboratory anticarcinogenic activity and suggested
potential toxicity profiles of these agents, translational clinical
chemopreventive trials to substantiate their efficacy in humans were
lacking at the time.[6,17,18]
Much of this work has been conducted by investigators from M. D.
Anderson Cancer Center (Houston) in carefully designed, double-blind,
placebo-controlled clinical chemoprevention trials.[3,17,18] These
studies focused on vitamin A and its synthetic analogs, collectively
referred to as retinoids. The retinoids appear to act by binding to a
specific set of retinoic acid receptors (RAR) and
retinoid-X-receptors (RXR). The binding of retinoids to these
receptors results in binding to specific nuclear sites and the
transcriptional activation of multiple downstream genes. Retinoids
function by inducing differentiation in cells that have lost normal
regulatory mechanisms. Whereas retinol and the synthetic retinoids
produce significant toxic effects if given in high doses, different
synthetic retinoids with different receptor-specific ties are being
developed, several of which have undergone extensive clinical
testing. Synthetic retinoids that have demonstrated activity in
various clinical trials to date include 13-cis-retinoic acid (13cRA)
in head and neck cancers, myelodysplasia, childhood neuroblastoma,
and juvenile chronic myelogenous leukemia; all-trans-retinoic acid
(ATRA) in acute promyelocytic leukemia (APL); etretinate in cervical
and skin cancers; and retinyl palmitate in lung cancer. Also,
9-cis-retinoic acid (9cRA), an RXR-specific ligand,
4-N-(4-hydroxyphenyl) retinamide (4-HPR), and other new vitamin A
derivatives are under active clinical investigation.[2,3,9,12]
The ability of retinoids to suppress lung carcinogenesis in animal
models was believed to result from changes in the expression of their
nuclear retinoid receptors, because these receptors play a proximal
role in the retinoid signaling pathway. Retinoids exert their actions
through activation of the nuclear retinoid receptors that act as
transcription factors for genes that influence cell growth and
differentiation. Therefore, changes in their expression may cause
aberrations in cells response to retinoids and alterations in
growth and differentiation regulation. It was found that RAR-b
expression is suppressed in many lung cancer cell lines, a finding
that implies a selective suppression of RAR-b
in malignant transformation. Selective suppression of RAR-b
in the early stages of carcinogenesis in the oral cavity and marked
upregulation of RAR-b after retinoid
treatment associated with clinical response have been confirmed, thus
giving RAR-b excellent potential as an
intermediate biomarker.[2-4,19] A pilot study of RAR-b
expression in specimens from a previous chemoprevention trial in
bronchial metaplasia revealed that only 55% of patients expressed RAR-b
before treatment, with some upregulation of RAR-b
expression taking place after retinoid treatment.
Retinoid receptor expression was compared in specimens from normal
and malignant lung tissues. All receptors were expressed in at least
89% of control normal bronchial tissue specimens from patients
without a primary lung cancer and in distant normal bronchus
specimens from patients with nonsmall-cell lung cancer. RAR-a,
RXR-a, and RAR-g were expressed in more
than 95% of the 79 nonsmall-cell lung cancer specimens, in
contrast to RAR-b, RAR-g,
and RXR-b expression, which were detected
in only 42%, 72%, and 76% of nonsmall-cell lung cancer
specimens, respectively. These findings provide further evidence for
implication of RAR-b, and possibly RAR-g
and RXR-b, in lung carcinogenesis.
Chemoprevention Trials in Bronchial Premalignant Lesions
Bronchial metaplasia, dysplasia, and sputum atypia are associated
with lung cancer and a history of smoking. Sputum atypia was examined
in a multi-center lung cancer screening, and was not found to predict
lung cancer development. Chemoprevention trials have investigated the
effect of different agents on bronchial metaplasia and dysplasia and
sputum atypia (Table 1). In a
small uncontrolled pilot trial of participants with at least a
15pack-year smoking history, Mathe et al observed a reduction
in bronchial metaplasia following treatment with etretinate, a
synthetic retinoid. In smokers with at least a 15pack-year
history, Arnold et al examined the effect of 6 months of treatment
with etretinate or placebo on sputum atypia and found no effect.
In a population with a heavier smoking history and exposure to
asbestos, McLarty et al observed no effect of b-carotene
and retinol on sputum atypia. In participants with at least a
20pack-year smoking history, Lee et al found no effect on 13cRA
on bronchial metaplasia, but bronchial metaplasia was reduced by
smoking cessation, suggesting that bronchial metaplasia is an acute
reaction to cigarette smoke exposure in active smokers.
The previously mentioned trials have relied on white-light
bronchoscopy for the detection of bronchial metaplasia and dysplasia.
A new technique using a laser incorporated into a bronchoscope was
reported to be 50% more sensitive in the detection of bronchial
dysplasia than standard white-light bronchoscopy. This technique is
based on the principle that light of specific wavelengths can
stimulate intrinsic cellular florophors, such as flavins,
riboflavins, nucleic acids, and proteins, to fluoresce, thereby
emitting a spectral pattern of light typical of that particular
tissue. Epithelial carcinogenesis is associated with altered levels
of these fluoroflors; by using fluorescence spectroscopy, normal,
dysplastic, and neoplastic tissues can be distinguished on the basis
of their spectral patterns. This new bronchoscopic technique is under
evaluation in chemoprevention trials as a method of enhancing the
detection of bronchial premalignancy in smokers and former smokers.[29-31]
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