Antioxidants

α- and β-Carotene and other Carotenoids

Carotenoids have been studied vigorously to see if these colorful compounds can decrease cancer risk. In ecological studies and early case-control studies it appeared that β-carotene was a cancer-protective agent. Randomized controlled trials of β-carotene found that the isolated nutrient was either neutral [141] or actually increased risk of lung cancer in smokers [142,143]. Beta-carotene may be a marker for intake of fruits and vegetables, but it does not have a powerful protective effect in isolated pharmacological doses.

However, there is a large body of literature that indicates that dietary carotenoids are cancer preventative (See Table 6). Alpha-carotene has been found to be a stronger protective agent than its well-known isomer β-carotene. Studies tend to agree that overall intake of carotenoids is more protective than a high intake of a single carotenoid. So, a variety of fruits and vegetables is still a better anti-cancer strategy than just using a single vegetable high in a specific carotenoid.

The richest source of α-carotene is carrots and carrot juice, with pumpkins and winter squash as a second most-dense source. There is approximately one μg of α-carotene for every two μg of β-carotene in carrots. The most common sources of β-cryptoxanthin are citrus fruits and red sweet peppers.

Lycopene

Of the various carotenoids lycopene has been found to be very protective, particularly for prostate cancer. The major dietary source of lycopene is tomatoes, with the lycopene in cooked tomatoes being more bioavailable than that in raw tomatoes. Several prospective cohort studies have found associations between high intake of lycopene and reduced incidence of prostate cancer, though not all studies have produced consistent results [144,145]. Some studies suffer from a lack of good correlation between lycopene intake assessed by questionnaire and actual serum levels, and other studies measured intakes among a population that consumed very few tomato products. The studies with positive results will be reviewed here.

In the Health Professionals Follow-up Study there was a 21% decrease in prostate cancer risk, comparing the highest quintile of lycopene intake with the lowest quintile. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of the lycopene intake) were associated with a 35% lower risk of prostate cancer. Furthermore, lycopene was even more protective for advanced stages of prostate cancer, with a 53% decrease in risk [146]. A more recent follow-up report on this same cohort of men confirmed these original findings that lycopene or frequent tomato intake is associated with about a 30–40% decrease in risk of prostate cancer, especially advanced prostate cancer [147].

In addition to the two reports above a nested case control study from the Health Professional Follow-up Study with 450 cases and controls found an inverse relation between plasma lycopene and prostate cancer risk (OR 0.48) among older subjects (>65 years of age) without a family history of prostate cancer [148]. Among younger men high plasma β-carotene was associated with a statistically significant 64% decrease in prostate cancer risk. So, the results for lycopene have been found for dietary intakes as well as plasma levels.

In a nested case-control study from the Physicians' Health Study cohort, a placebo-controlled study of aspirin and β-carotene, there was a 60% reduction in advanced prostate cancer risk (P-trend = 0.006) for those subjects in the placebo group with the highest plasma lycopene levels, compared to the lowest quintile. The β-carotene also had a protective effect, especially for those men with low lycopene levels [149].

In addition to these observational studies, two clinical trials have been conducted to supplement lycopene for a short period before radical prostatectomy. In one study 30 mg/day of lycopene were given to 15 men in the intervention group while the 11 men were in the control group were instructed to follow the National Cancer Institute's recommendations to consume at least 5 servings of fruits and vegetables daily. Results showed that the lycopene slowed the growth of prostate cancer. Prostate tissue lycopene concentration was 47% higher in the intervention group. Subjects that took the lycopene for 3 weeks had smaller tumors, less involvement of the surgical margins, and less diffuse involvement of the prostate by pre-cancerous high-grade prostatic intraepithelial neoplasia [150]. In another study before radical prostatectomy surgery 32 men were given a tomato sauce-based pasta dish every day, which supplied 30 mg of lycopene per day. After 3 weeks serum and prostate lycopene levels increaed 2-fold and 2.9-fold, respectively. PSA levels decreased 17%, as seen also by Kucuk et al [150]. Oxidative DNA damage was 21% lower in subjects' leukocytes and 28% lower in prostate tissue, compared to non-study controls. The apoptotic index was 3-fold higher in the resected prostate tissue, compared to biopsy tissue [151]. These intervention studies raise the question of what could have been done in this intervention was longer and combined synergistically with other effective intervention methods, such as flax seed, increased selenium and possibly vitamin E, in the context of a diet high in fruits and vegetable?

Vitamin C

Vitamin C, or ascorbic acid, has been studied in relation to health and is the most common supplement taken in the USA. Low blood levels of ascorbic acid are detrimental to health (for a recent article see Fletcher et al [152]) and vitamin C is correlated with overall good health and cancer prevention [153]. Use of vitamin C for cancer therapy was popularized by Linus Pauling. At high concentrations ascorbate is preferentially toxic to cancer cells. There is some evidence that large doses of vitamin C, either in multiple divided oral doses or intravenously, have beneficial effects in cancer therapy [154-156]. Oral doses, even in multiple divided doses, are not as effective as intravenous administration. Vitamin C at a dose of 1.25 g administered orally produced mean peak plasma concentrations of 135 ± 21 μmol/L compared with 885 ± 201 μmol/L for intravenous administration [154].

While vitamin C is quite possibly an effective substance, the amounts required for these therapeutic effects are obviously beyond dietary intakes. However, intravenous ascorbate may be a very beneficial adjuvant therapy for cancer with no negative side effects when administered properly.

Other Antioxidants

There are many more substances that will have some benefit for cancer therapy. Most of these substances are found in foods, but their effective doses for therapy are much higher than the normal concentration in the food. For example, grape seed extract contains proanthocyanidin, which shows anticarcinogenic properties (reviewed by Cos et al \ [157]. Also, green tea contains a flavanol, epigallocatechin-3-gallate (EGCG), which can inhibit metalloproteinases, among several possible other mechanisms [158]. And there are claims for various other herbal substances and extracts that might be of benefit, which are beyond the scope of this review.