Nutrition: Antioxidants and Fat

Epidemiologic studies have provided evidence about the nature of dietary deficiencies
and excesses that have influenced the risk of lung cancer. The
most consistent association, gathered from case-control and
cohort studies, was that increased consumption of fresh vegetables
and fruits lowered the risk in men and women, in current
or former smokers, or particularly among never-smokers,
and for all histologic types. The higher levels of consumption,
when compared with the lowest reference level, tended to be
associated with 40% to 50% reduction in the smoking-, age-,
and gender-adjusted RR of lung cancer of various cell types.
Various antioxidants were considered as putative chemopreventive
nutrients, but a major focus has been on the provitamin
A carotenoids, particularly -carotene. Some investigators
have reported that -carotene was most protective in current
or heavy smokers, whereas others have found that -carotene
or carotenoids were most protective in former smokers or in
nonsmokers. 109–113 In a population-based case-control study
of lung cancer in nonsmokers conducted in New York State,
Holick et al. 114 concluded that the increased consumption of
raw (not cooked) fruits and vegetables was associated with a
significantly reduced risk for lung cancer. Dietary -carotene
(odds ratio 0.70; 95% CI, 0.50 to 0.99), but not dietary
retinol (vitamin A), was significantly associated with risk reduction
for lung cancer in nonsmoking men and women.
By the mid-1980s, large-scale randomized clinical trials
of -carotene, -carotene plus retinol, or -carotene and/or
vitamin E were initiated in subjects at increased risk of lung
cancer. The -tocopherol/ -carotene trial (ATBC) in Finland
was a primary prevention trial among over 29,000 male smokers
of 50 to 69 years of age. The 2 2 factorial design evaluated
20-mg -carotene and/or 50-IU -tocopherol (vitamin E) daily
for 6.5 years. These doses represented a fivefold excess over the
median intake of -tocopherol and a 10-fold excess over the median
intake of -carotene in the general population. When compared
with placebo groups, supplementation with vitamin E did
not alter lung cancer incidence; however, participants receiving
-carotene alone or in combination with -tocopherol had significantly
higher lung cancer incidence (RR 1.18; 95% CI,
1.03 to 1.36). The excess lung cancer incidence was demonstrable
after the initial 18 months. The randomized design and
analysis controlled for cigarette smoking history. 115
The Carotene and Retinol Efficacy Trial (CARET) was a
multicenter randomized trial to test whether oral administration
of the combination of -carotene (30 mg/day) and retinyl
palmitate (25,000 IU/day) would decrease lung cancer incidence
in high-risk populations of female smokers and male
smokers and/or exposed asbestos workers. In the treatment
group, when compared with the placebo group, the RR, after
an average follow-up of 4 years, of death from lung cancer was
1.46 (95% CI, 1.07 to 2.00). The RRs were elevated in current
smokers. 116,117 After 12 years of follow-up in the placebo arm
of CARET, a significant protective effect was observed with
total fruit or cruciferous vegetable consumption. The RR for
highest versus lowest quintile of total fruit consumption in the
placebo arm was 0.56 (95% CI, 0.39 to 0.81); for cruciferous
vegetables, the RR was 0.68 (95% CI, 0.45 to 1.04). 118
The Physicians’ Health Study was a long-term randomized
trial organized to test the effect of aspirin on cardiovascular disease
incidence. -Carotene (50 mg) was added in a 2 2 factorial
design. In this healthy male population with 11% current
cigarette smokers, and after an average follow-up of 12.5 years,
the investigators concluded that the intervention did not reduce
or increase the incidence of lung cancer (RR 0.93). 119,120
It is disconcerting and challenging to reflect about the
lack of demonstrable benefit or even an adverse outcome of
increased risk of lung cancer in smoking men and women
participating in various chemoprevention clinical trials. The
results of these clinical trials would appear to contradict the
epidemiologic observational studies. -Carotene is only one of
many carotenoids ingested in vegetables and fruits and, under
conditions of increased oxidative stress as in exposure to cigarette
smoke or asbestos, -carotene can be oxidized to an epoxide
or reactive electrophilic derivative that would be mitogenic
rather than inhibitory of cell proliferation. Handelman et al.
exposed human plasma to the gas phase of cigarette smoke and
observed oxidative disruption of carotenoids and -tocopherol.
In addition to carotenoids, fresh fruits and vegetables contain
other micronutrients including vitamin C, folic acid, flavones,
isoflavonoids (e.g., soy products), protease inhibitors, thiocyanates,
and indoles (e.g., indole-3-carbinol in Brassica vegetables).
Methyl-deficient diets result from low consumption
of fruits and vegetables (folate) and of poultry, fish, and dairy
products (methionine). Folic acid, methionine, and choline are
interrelated in methyl group metabolism. Selective growth and
transformation of cells can result from DNA hypomethylation
and overexpression of proto-oncogenes or hypermethylation of
CpG islands in promoter regions that may attenuate the expression
of tumor suppressor genes. In the cohort study of health
professionals by Feskanich et al., 122 both fruits and vegetables,
consumed with regular frequency were protective for lung cancer
in women and men who never smoked (RR 0.63; 95%
CI, 0.35 to 1.12). In the study by Shen et al., 123 the association
with folate was most apparent among former heavy smokers.
Various chemopreventive mechanisms of action by micronutrients
and nonnutritive phytochemicals in fruits and
vegetables have been suggested by in vitro and animal feeding
experimental studies. Chemoprevention refers to the use of
natural or synthetic agents to reverse, prevent, or delay the
progression of preneoplastic or preinvasive neoplastic disease.
The complex interrelated mechanisms by which substances
in vegetables and fruits may inhibit carcinogenesis include
regulation of cell differentiation, “quenching” or “trapping”
of oxygen or hydroxyl free radicals, preventing the formation
of electrophilic metabolites from precursor compounds by inhibiting
the enzymatic activation pathway (e.g., cytochrome
P450) or by inducing the detoxification pathway (e.g., glutathione
S-transferase [GST]), enhancing DNA methylation,
inhibiting the expression of oncogenes, and stimulating immune
function. 124
Lung cancer mortality is significantly positively correlated
in various countries with per capita fat availability and consumption.
An increased risk of lung cancer has been reported in association
with high dietary intake of foods rich in fat and cholesterol,
or with elevated indices of abdominal adiposity. However, the
positive association of dietary cholesterol and lung cancer risk has
not been reflected in studies of serum cholesterol levels. Shekelle
et al. 125 have hypothesized that a low, not elevated, serum cholesterol
is predictive of increased risk of lung cancer, particularly
in the subgroup of the population with low intake of -carotene.
Studies of the effects of dietary cholesterol and total and saturated
fat have attempted to control for the confounding effects of gender,
smoking status, and total intake of energy, fruits, vegetables,
and carotenoids. In the study by Alavanja et al. 126 in female
smokers in Missouri, a significant association was noted between
intake of saturated fat and lung cancer. Despite the positive association
with dietary fat, lung cancer risk was not associated
with increasing body mass; indeed, several studies have described
elevated risks in subgroups in the lowest categories of body mass
index, which were not explained by confounding from cigarette
smoking. 127,128 Although the potential association of specific
histologic types of lung cancer with body fat distribution should
be investigated further as suggested by Olson et al.,129 the considerable
inconsistencies in the associations with cholesterol and fat
do not suggest that dietary fat intake has a major etiologic role.