Lycopene, Tomatoes, Tomato-Based Food Products and the Prevention of Cancer

Based on my review of the reliable and credible scientific literature regarding the effects of tomato and tomato-based food product consumption and of dietary supplementation with lycopene on various cancers, I conclude that there is significant scientific agreement in support of the following health claims:

• Lycopene may reduce the risk of cancer.
• Lycopene may reduce the risk of prostate cancer.
• Lycopene may reduce the risk of lung cancer.
• Lycopene may reduce the risk of gastric cancer.
• Lycopene may reduce the risk of colorectal cancer.
• Lycopene may reduce the risk of breast cancer.
• Lycopene may reduce the risk of cervical cancer.
• Lycopene may reduce the risk of endometrial cancer.
• Lycopene may reduce the risk of ovarian cancer.
• Lycopene may reduce the risk of pancreatic cancer.
• Tomatoes may reduce the risk of cancer.
• Tomatoes may reduce the risk of prostate cancer.
• Tomatoes may reduce the risk of lung cancer.
• Tomatoes may reduce the risk of gastriccancer.
• Tomatoes may reduce the risk of colorectal cancer.
• Tomatoes may reduce the risk of breast cancer.
• Tomatoes may reduce the risk of cervical cancer.
• Tomatoes may reduce the risk of endometrial cancer.
• Tomatoes may reduce the risk of ovarian cancer.
• Tomatoes may reduce the risk of pancreatic cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cancer.
• Lycopene-containing tomato-based foods may reduce the risk of prostate cancer.
• Lycopene-containing tomato-based foods may reduce the risk of lung cancer.
• Lycopene-containing tomato-based foods may reduce the risk of gastric cancer.
• Lycopene-containing tomato-based foods may reduce the risk of colorectal cancer.
• Lycopene-containing tomato-based foods may reduce the risk of breast cancer.
• Lycopene-containing tomato-based foods may reduce the risk of cervical cancer.
• Lycopene-containing tomato-based foods may reduce the risk of endometrial cancer.
• Lycopene-containing tomato-based foods may reduce the risk of ovarian cancer.
• Lycopene-containing tomato-based foods may reduce the risk of pancreatic cancer.

I. Lycopene

A. Chemistry
Lycopene (C₄₀H₅₆) is a natural fat-soluble pigment found in plants where it serves as an accessory light-gathering pigment and free radical quencher. This carotenoid is an open chain polyisoprenoid with 11 conjugated double bonds. Lycopene occurs in food sources predominantly as all-trans-lycopene. Various cis-isomers also are found in human blood and tissues, suggesting post-ingestive isomerization. Because lycopene is acyclic it does not serve as a substrate for ß-carotene 15,15’-dioxygenase and therefore cannot be converted to vitamin A.^1-4

B. Food Sources
The major food sources of lycopene are raw red or pink grapefruit (1419 mcg of lycopene per 100 g edible fruit), raw watermelon (4532 mcg of lycopene per 100 g edible fruit), raw tomatoes (year-round average: 2573 mcg of lycopene per 100 g edible fruit) and processed food products containing tomatoes (tomato juice, 9037 mcg of lycopene per 100 g juice; canned whole tomatoes, 4035 mcg of lycopene per 100 g edible portion; tomato sauce, 15152 mcg of lycopene per 100 g sauce; tomato puree, 21754 to 28764 mcg of lycopene per 100 g puree; tomato paste, 29330 mcg of lycopene per 100 g paste; tomato soup, 14596 mcg of lycopene per 100 g soup; catsup, 17007 mcg of lycopene per 100 g of catsup).⁵ Little lycopene is lost during heat processing; for example, the six-fold concentration of tomatoes during the conversion of whole tomatoes into tomato paste is accompanied by a six-fold concentration of lycopene.⁶ Similarly, between 90% and 95% of the total lycopene in tomatoes is in the form of trans-lycopene, with the remainder as various cis-isomers; the ratio of trans- to cis-isomers is not affected by the conversion of raw tomatoes into tomato paste.^2,7-10

Lycopene in foods and food products is extraordinarily stable.¹¹ Estimates of losses in total lycopene content during the heat processing of tomatoes into tomato juice, paste, soup or sauce have ranged from nil to less than 15% ; ^9,12-14 Further cooking on a stove for 1 hour did not affect the product’s total lycopene content,^12,14 although the ratio of trans-lycopene to cis-lycopene was decreased slightly.¹² Storage of processed tomato juice at 25o C or 37o C for 12 months had no effect on total lycopene content, while storage at 4o C for 12 months reduced total lycopene content by 3%.¹²

C. Bioavailability
Lycopene naturally occurs in plants and is closely associated with the organic matrix of plant cells.^15,16 It appears that lycopene must be released from this matrix in order for absorption to occur.^16,17 This release is effected by gastric acidity^18,19 and by thermal processing of foods containing lycopene prior to their ingestion.^8,11,20 Several investigators have reported that the bioavailability of lycopene (assessed from analysis of acute and subacute changes in post-ingestive circulating total lycopene concentrations) is increased following the conversion of raw tomatoes into juice, paste or puree.^8,20-23 Others have reported that the bioavailability of lycopene in the tomato oleoresin extracts supplied as dietary supplements is greater than is the bioavailability of the lycopene in raw tomatoes but is not different from the bioavailability of lycopene in tomato juice.²⁴

Following release from its native organic matrix, or after ingestion as an extract, free lycopene is absorbable only after its incorporation into micelles.² Cis-isomers maybe more readily absorbed than trans-isomers (as has been found in ferrets¹⁹) as a consequence of the greater solubility in mixed micelles of cis-isomers.2 Any conditions or factors (such as hypochlorhydria, achlorhydria, biliary insufficiency, liver failure, the consumption of a fat-free diet, etc.) that interfere with or reduce postprandial micellar formation will decrease the absorbability of ingested lycopene.^16,25 Conversely, conditions that promote the solubility of lycopene in mixed micelles, such as the presence of monounsaturated fatty acids, will increase the absorbability of ingested lycopene (although low-fat diets appear to have no effect ^26,27).^21,28 Micellar dispersal at the brush border releases lycopene to enter enterocytes via passive diffusion; within enterocytes, lycopene is incorporated into chylomicrons for secretion into the mesenteric lymph system 2 to 6 hours after the consumption of lycopene-containing foods.^2,8 Acting on chylomicrons in the circulation, lipoprotein lipase releases lycopene for uptake by peripheral tissues and organs, including the liver, which repackages lycopene into lipoproteins that are secreted into the circulation 12 to 48 hours later.⁸

In the only study reporting quantitative data on lycopene absorption obtained through the application of compartmental modeling techniques to serum appearance and disappearance data, healthy men were reported to absorb an average of 4.7 mg of total lycopene from daily intakes ranging from 10 to 120 mg.²⁹ The amount of lycopene absorbed was independent of intake, suggesting the possibility of the potential for saturation of lycopene absorptive mechanisms. Mean efficiencies of absorption of oral lycopene ranged from 34% (10 mg of lycopene consumed) to 5% to 7% (60 mg to 120 mg of lycopene consumed). These estimates of lycopene absorption are greater than that obtained through the use of an in vitro model, which produced an estimate that about 3% of the total lycopene in a stir-fried meal of fresh vegetables was incorporated into micelles (and therefore absorbable),³⁰ an in vivo model of human micellar formation in situ, which produced an estimate of the efficiency of lycopene absorption of about 2%³¹ and an in vivo model of lycopene absorption through association with triglycerides, which resulted in an estimate of the efficiency of lycopene absorption of about 2.5%.³²

The bioavailabilities of synthetic lycopene preparations have been compared to the bioavailabilities of the lycopene in raw tomatoes and processed tomato products. The bioavailabilities of the synthetic lycopene in microencapsulated beadlets (Lycopene 5% TG, D.S.M. N.V., Heerlen, The Netherlands; LycoVit 10%, BASF, Ludwigshafen, Germany; containing isomeric distributions of lycopene similar to that found in raw tomatoes^23,33), the extracted “natural source” lycopene in a bead formulation (Lyc-O-Mato™ 6%, LycoRed Natural Products Industries Ltd., Beer-Sheva, Israel) and lycopene in cooked tomato soup have been found to be nearly identical.23,34 Consistent with the differences in the bioavailabilities of lycopene in raw and processed tomato-based foods,^8,20-23 the bioavailability of synthetic lycopene has been reported to be significantly greater than the bioavailability of lycopene in unprocessed (raw) tomato juice.²³

II. The Relationships among the Consumption of Tomatoes and Tomato-Based Foods Containing Lycopene, Dietary Supplementation with Lycopene and Typical Circulating Lycopene Concentrations in Humans

The measured serum or plasma total lycopene concentrations of over 95% of the subjects in a vast array of studies have ranged between 0.1 x 10-⁶ M and 2 x 10-⁶ M.^{7,10,12,22,29,33-148} These reports are consistent with population survey data that have produced the estimates of serum total lycopene concentrations in the U.S. summarized in Table 1.

Data from several studies confirm that circulating total lycopene concentrations decline among older adults.^43,121,145 In one study, the mean serum total lycopene concentration of a cohort of men with a mean age of 73 years was only 57% of the mean serum total lycopene concentration of a cohort of men with a mean age of 24 years.¹²¹

Table 2. Daily lycopene intakes estimated from data obtained in the National Health and Nutrition Examination Survey III (NHANES III) between 1988 and 1994.¹⁵⁴

Data from the National Health and Nutrition Examination Survey III (NHANES III) indicate that cigarette smokers have significantly lower serum total lycopene concentrations than do nonsmokers.150 This conclusion is consistent with data obtained from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.³⁸

Less data are available concerning lycopene intake. Several surveys (1986 Continuing Survey of Food Intake by Individuals;¹⁵¹ 1992 National Health Interview Survey;¹⁵² Nutritional Factors in Eye Disease Study¹⁴⁶) have suggested that mean daily lycopene intake in the U.S. is between 1.6 and 2.6 mg.¹⁴⁹ However, data obtained from the 83,234 participants in the Nurses’ Health Study indicates that those women consumed more lycopene on a routine basis (median intake: 6077 mcg).¹⁵³ Data obtained from the participants in the NHANES III study (Table 2) contradict these reports, with mean daily lycopene intakes for adults ranging from 4332 mcg to 12656, and median daily lycopene intakes for adults ranging from 842 mcg to 5211 mcg, depending on sex and age.¹⁵⁴ Interestingly, both mean and median daily lycopene intakes were greater among pregnant and lactating adult women than among nonpregnant and nonlactating premenopausal adult women. However, with the exception of men aged 19 to 30 years, over 25% of the participants in the NHANES III study reported no consumption of lycopene-containing foods (and between 10% and 25% of men aged 19 to 30 years reported no consumption of lycopene-containing foods).

Daily lycopene intakes estimated from USDA nutrient composition⁵ and food consumption data¹⁵⁵ suggest that lycopene intakes may well average 3- to 10-fold higher than is indicated by other estimates. According to USDA data, per capita consumption of fresh tomatoes averaged 23.3 g daily in 2002 (providing about 0.6 mg of lycopene daily) and is forecast to average 23.7 g daily in 2003 (providing about 0.6 mg of lycopene daily). The consumption of all other tomato-containing foods averaged 87.8 g daily in 2002 (equivalent to 0.7 tomatoes daily⁵) providing between 9 and 27 mg of lycopene daily, depending upon the specific foods and food products consumed) and is forecast to average 89.4 mg daily in 2003 (providing between 9 and 27 mg of lycopene daily, depending upon the specific foods and food products consumed). These data indicate that total daily lycopene consumption averaged between 9 and 28 mg daily in the U.S. in 2002 and 2003. According to these same USDA data, the consumption of tomatoes, tomato-containing foods and food products and lycopene have not changed since 1990.

Data from the 38,445 women participating in the Women’s Health Study indicate that lycopene intake is determined primarily by the consumption of tomatoes and tomato-based food products.¹⁵⁶ Among 946 women participating in the Women’s Health Initiative, serum total lycopene concentration was independently significantly correlated with the consumption of fresh tomatoes, cooked tomatoes, tomato juice, tomato sauce and tomato salsa.⁴³ The results of several human studies have demonstrated that serum or plasma total lycopene concentration is significantly correlated with lycopene intake in healthy men and women^{43,65,68,141,144,146} and is unvarying within individuals over a number of years (probably reflecting the relative stability of adult dietary habits).^{60,66,77,92,98,111} Therefore, it has been asserted that the measurement of circulating total lycopene concentration in single blood samples provides predictors of long-term lycopene intakes that are sufficiently valid for epidemiologic studies.¹¹¹

In contrast, intentional reduction in lycopene intake produces a significant decrease in circulating lycopene concentrations.^124,125,157 Furthermore, increasing lycopene intake has produced significant increases in serum or plasma total lycopene concentrations in healthy men and women.^{12,22,24,34,77-79,85,89,124-126,138} Similarly, increased consumption of tomatoes and tomato-containing foods and food products significantly increased serum or plasma total lycopene concentrations in healthy men and women^{23,24,36,43,47,51,69,70,78,79,85,89,91,109,110,122-125,130,134,158} as well as in women with breast cancer,^66,92 men and women with colorectal adenomas,⁹⁸ men with prostate cancer,¹⁰⁵ men and women with diabetes,¹³⁶ male and female renal transplant recipients,¹⁰⁰ male and female cancer survivors⁶³ and lactating women.³⁸

III. Cancer

A. Cancer Mortality
Cancer is the second leading cause of death in the U.S.¹⁵⁹ The American Cancer Society forecast 556,500 deaths from cancer in 2003.¹⁵⁹ Overall, the 5-year relative survival rate is 62%.159 The rate of survival is drastically reduced by the presence of malignancy. Between 60% and 65% of the estimated 285,900 men dying from cancer in 2003 will die from lung, bronchial, prostate or colorectal cancers. About 75% of the estimated 270,600 women dying from cancer in 2003 will die from cancers of the lungs, bronchi, breast, colon or rectum. In addition to the termination of these cases by death, about 675,300 men and 658,800 women are predicted to become newly-diagnosed with cancer during 2003, resulting in a net increase of about 10% in the number of individuals in the U.S. with cancer. Total cancer-related health care costs during 2002 were approximately 171.6 billion dollars (approximately 61 billion dollars for direct medical expenditures).¹⁵⁹

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
Mouse C3H/10T1/2 embryonic fibroblasts are well-studied and are known to undergo neoplastic transformation in response to many chemical and physical carcinogens in a dose-dependent manner.^160,161 Following pretreatment of cultures of C3H/10T1/2 cells with the cell transformation inducing agent, methylcholanthrene, the addition of lycopene (3 x 10-6 M) to the culture medium significantly inhibited the generation of foci of transformed cells, producing about 50% inhibition.¹⁶¹ This inhibition occurred only upon exposure to lycopene during the postinitiation period; lycopene (10 x 10-6 M) exposure concurrent with exposure to methylcholanthrene did not affect transformation. The neoplastic transformation-inhibiting activity of lycopene was strongly correlated with lycopene-induced upregulation of expression of connexin 43¹⁶² and stimulation of intercellular gap junctional communication.163 In various cancers, including human prostate cancer, the expression of connexin 43 is inversely proportional to the degree of disease progression and the induction of increased connexin 43 expression in epithelial cells from prostate tumors has been accompanied by deceleration of proliferation and the induction of cellular differentiation (i.e., reversal of disease progression).164 Lycopene (3 x 10-⁶ M) also has significantly stimulated expression of connexin 43 and intercellular gap junctional communication while significantly inhibiting proliferation in cultures of human KB-1 oral tumor cells.165 Similarly, lycopene (0.1 x 10-⁶ M) significantly stimulated gap junctional communication in cultures of human fetal skin fibroblasts, although in that cell culture system lycopene did not affect connexin expression.¹⁶⁶

Gap junction channels consist of apposed cylindrical aggregates of six subunits each in adjacent cell membranes and are found throughout the body.^167,168 Extracellular loops that extend from the transmembrane-spanning domains of each of the six protein subunits across intercellular space interact with similar loops extending from an adjacent cell and establish the junction. At each gap junction, each cell contributes a hemiconnexon consisting of six identical protein units (connexins) assembled radially to encircle and enclose a water-filled pore that allows direct cytoplasmic-to-cytoplasmic communication of ions and low molecular weight water-soluble compounds (such as cyclic AMP) via passive diffusion down concentration gradients between the two cells without loss to the extracellular space. A variety of connexins exist within the human body; connexin 43 is the most widely distributed.

An important function of gap junctions is to serve as conduits for antiproliferative signals generated by proliferation-inhibited normal cells and that act to suppress the proliferation of carcinogen-initiated cells thereby preventing their transformation into tumor cells.^169,170 Cells deficient in the ability to receive or respond to such signals originating from proliferation-inhibited normal cells as a result of reduced or absent expression of connexin genes (as occurs in most human tumor cell lines) are at a relative proliferative advantage. Conversely, agents that increase gap junctional communication between cells deficient in this function and proliferation-inhibited normal cells should produce inhibition of the proliferation of previously-deficient cells. However, increased gap junctional communication between cells deficient in this function and proliferation-inhibited normal cells requires that the functionally deficient cells not have progressed from the initiation or promotion stages of carcinogenesis to the gap junctional communication-resistant stage of cell transformation into tumor cells.^169,171 This apparent requirement is consistent with reports that many tumor promoting substances inhibit gap junctional communication and that potency as tumor promoter is correlated with potency as inhibitor of connexin expression and gap junctional communication.¹⁶⁸ In addition, reduced expression of connexin genes may be a required precursor lesion preceding cell transformation and stimulation of connexin gene expression with resultant increase in gap junctional communication may be a key cancer-preventing property of connexin-inducing agents.^167,168

C. Human Studies Provide Scientific Support for the Conclusion that Risk of Developing Cancer is Reduced by the Consumption of Lycopene, or Tomatoes or Tomato-Based Foods Containing Lycopene
Oxidative damage to DNA can produce genetic changes associated with the initiation and progression of cancer.^172,173 Oxidative damage to DNA has been proposed as a biologically significant contributor to the development of colon, breast, rectum and prostate cancers.^174,175 Several products of DNA base oxidation, including 8-hydroxyguanine, 2-hydroxyadenine, 5-hydroxycytosine, 5-hydroxyuracil and formyluracil, are known to be mutagenic in concentrations that mimic their frequency in endogenous DNA.^176-179 It has been reasoned that, based on the available experimental evidence, the extent of oxidative DNA damage in human cells is a biomarker with some ability to predict risk for the development of cancer and reduction in the extent of oxidative DNA damage in human cells is consistent with reduced risk for the development of cancer.¹⁸⁰

Lycopene has been demonstrated to be the most potent free radical antioxidant among the carotenoids.^51,181,182 The potential for the consumption of foods providing significant amounts of dietary lycopene to exert chemoprotection against oxidative damage to DNA was examined in healthy nonsmoking men.¹⁸³ Compared to the end of a 2-week period of intentional lycopene depletion, after 2 weeks of dietary supplementation with tomato juice containing 40 mg of lycopene daily, the number of endogenous DNA strand breaks was significantly reduced in circulating lymphocytes. Although endogenous DNA strand breaks was significantly reduced, this short-term consumption of additional lycopene-containing tomato-based food product was insufficient to produce a statistically significant decrease in the physiologic effector of DNA strand breaks, oxidative base damage. In contrast, the ingestion of a single serving of fresh tomatoes (8 g per kg body weight) by healthy men and women significantly reduced the endogenous production of oxidized DNA base adducts in circulating lymphocytes and leukocytes.⁷

Consistent with the conclusion that increased lycopene intake reduces endogenous damage to DNA, 2 weeks of dietary supplementation with tomato puree containing 7 mg of lycopene daily significantly reduced the number of exogenously-induced DNA strand breaks in circulating lymphocytes harvested from healthy women.⁸⁵ This chemopreventive effect was accompanied by significant increases in plasma total lycopene concentration and lymphocyte lycopene content. Both plasma total lycopene concentration and lymphocyte lycopene content were significantly inversely correlated with the extent of exogenously-induced oxidative damage to DNA. In another experiment in which total supplemental lycopene exposure was similar, lymphocytes harvested from healthy men and women whose diets were supplemented with semi-purified lycopene (15 mg daily) for 1 week exhibited significantly increased resistance to exogenously-induced oxidative damage to DNA.¹⁸⁴ The magnitude of effect was reflective of the extent to which dietary supplementation with lycopene produced increase in plasma total lycopene concentration. Similarly, lymphocytes harvested from healthy women supplemented with tomato puree containing 16.5 mg of lycopene exhibited significantly greater resistance to exogenously-induced DNA oxidation than was exhibited by lymphocytes harvested from healthy women whose diets were not supplemented,¹⁵⁸ and the consumption of a single serving of fresh tomatoes (8 g of tomatoes per kg body weight) significantly reduced the frequency of oxidative DNA base damage in circulating white blood cells.¹⁸⁵

In an in vitro test system, both hydrophilic and lipophilic extracts of fresh tomatoes, tomato paste and tomato puree significantly inhibited oxidative reactions catalyzed by xanthine oxidase and neutrophil-derived myeloperoxidase, major in vivo physiologic producers of superoxide, hydrogen peroxide and hypochloric acid.¹⁸⁶ In addition, the lipophilic extracts significantly inhibited copper-catalyzed oxidation of linoleic acid (lipid peroxidation). In confluent cultures of mouse C3H/10T1/2 embryonic fibroblasts, lycopene (1 x 10-⁶ M) significantly inhibited lipid peroxidation.¹⁶³

The published scientific evidence strongly supports the conclusion that the risk of developing any cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.

D. Human Studies Provide Significant Scientific Support for the Conclusion that Risk for Dying from Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
The findings of three studies support the conclusion that tomato and tomato-based food product consumption or dietary supplementation with lycopene reduce the risk of dying of cancer.^57,58,187 The results of a 5-year prospective study of 1,271 men and women aged 66 years or older indicated that the age-adjusted risk of dying from any cancer was significantly reduced by 50% (95% CI: 0.3, 0.8) in individuals who consumed an average of more than 1 serving of tomatoes weekly, compared to the risk of dying from any cancer of individuals who consumed an average of less than 1 serving of tomatoes weekly.¹⁸⁷ In another 8-year prospective study of 929 men and 1,424 women, the geometric mean serum total lycopene concentration of the subjects who died from cancer (0.28 x 10-⁶ M) was significantly lower than the geometric mean serum total lycopene concentration of the subjects who did not die during the study (0.37 x 10-⁶ M).⁵⁸

In a 9-year prospective study of 949 men and 1,495 women, 48 men and 28 women died from cancers.⁵⁷ Among these 2,444 subjects, the geometric mean serum total lycopene concentrations of the subjects who died from cancer (men: 0.16 x 10-⁶ M; women: 0.22 x 10-⁶ M) were significantly lower than the geometric mean serum total lycopene concentrations of the subjects who did not die during the study (men: 0.21 x 10-⁶ M; women: 0.31 x 10-⁶ M). The application of Cox’s proportional hazard model to the data from the entire cohort revealed that the multivariate-adjusted risk of death from any cancer was significantly reduced among those subjects with serum total lycopene concentrations in the highest tertile of serum total lycopene concentrations, compared to the risk among those subjects with serum total lycopene concentrations in the lowest tertile of serum total lycopene concentrations (hazard ratio: 0.37; 95% CI: 0.19, 0.72). This relationship was strengthened when only deaths occurring after the first three years of the study were included (hazard ratio: 0.36; 95% CI: 0.21, 0.61), when the analysis was restricted to only non-smoking subjects and only deaths occurring after the first three years of the study were included (hazard ratio: 0.33; 95% CI: 0.12, 0.90) and when the analysis was restricted to only subjects with serum total cholesterol concentrations greater than 250 mg/dL and only deaths occurring after the first three years of the study were included (hazard ratio: 0.33; 95% CI: 0.12, 0.90).

The published scientific evidence strongly supports the conclusion that the risk for dying from any cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based foods containing lycopene.

IV. Prostate Cancer

Prostate cancer is the leading cause of newly-diagnosed cancer in males in the US.¹⁵⁹ About 220,900 new cases of prostate cancer were forecast for the US for the year 2003, while nearly 30,000 men in the US were expected to die from this disease that year.¹⁵⁹ When all stages of prostate cancer are combined, the 5-year relative survival rate is 97%, 10-year relative survival is 79% and 15-year relative survival is 57%.¹⁵⁹

A. Pathogenesis of Prostate Cancer
Prostate cancer results from the proliferation of epithelial cells located predominantly in the peripheral zone of the prostate gland.^188,189 Carcinogenesis in the prostate occurs in a multistage process involving a series of genetic alterations with progression through a variety of pathways from precancerous lesions, including proliferative inflammatory atrophy and low-grade prostatic intraepithelial neoplasia, to a high-grade focus of accelerated proliferation without invasion of the basement membrane (“high-grade prostatic intraepithelial neoplasia”; HGPIN) through the development of a small latent androgen-dependent carcinoma to higher-grade androgen-independent metastatic disease.^188-194 HGPIN is recognized as a reversible precursor to prostate cancer.^188-194

Reactive oxygen species (such as the hydroxyl radical OH?) may be implicated in the pathogenesis of prostate cancer. A common early event in both HGPIN and prostate cancer is inactivation of the GSTP1 gene coding for the glutathione S-transferase P1 detoxification enzyme that catalyzes the conjugation of reactive oxygen species to glutathione within the prostate; elevated reactive oxygen activity results.¹⁹³ Evidence from two human studies suggests that oxidative changes in prostate tissue DNA (mutagenic lesions of adenine and guanine residues typical of those induced by hydroxyl radicals) are significantly increased in cancerous prostate tissue.^195,196 In addition, the extent of carcinogenic change was significantly correlated with the extent of hydroxyl radical-induced DNA damage.¹⁹⁵

The insulin-like growth factors (IGF-I and IGF-II) are circulating mitogens that interact with target cells via the cell membrane-bound IGF-receptor to influence the regulation of cell proliferation, differentiation, apoptosis and neoplastic transformation.^197,198 In particular, IGF-I is a potent mitogen that stimulates DNA synthesis and the progression of the cell cycle from the G1 phase to the S phase while also stimulating the expression of proapoptotic Bcl proteins and suppressing the expression of antiapoptotic Bax proteins.199 Epithelial cells harvested from noncancerous human prostate glands have demonstrated an abundance of IGF-I receptors²⁰⁰ and the in vivo proliferation of normal murine prostate epithelial cells appears to be IGF-I-dependent.²⁰¹

There is evidence that the risk of neoplastic transformation within a cell population increases as the proliferation rate of cells within the population increases,^202,203 suggesting that IGF-I availability to IGF-I-dependent tissues (such as the prostatic epithelium) contributes to risk of developing tissue-specific cancer.²⁰¹ Furthermore, increased IGF-I availability may accelerate the proliferation and clonal expansion of epithelial undergoing the process of neoplastic transformation.²⁰¹The dependence of human prostate cancer on IGF-I is suggested by the results of transplantation studies in which the proliferation of human androgen-independent PC-3 prostate cancer cells was curtailed following transplantation into IGF-I deficient mice but not after transplantation into normal mice.²⁰¹ Human prostate epithelial cells in primary culture proliferate in response to the addition of IGF-I to the culture medium; maximal response was observed with medium IGF-I concentration of 10 ng/ml and half-maximal response was observed at 1 ng/ml.²⁰⁰ There is evidence that prostate-specific antigen acts to increase circulating and perhaps local concentrations of free IGF-I by cleaving IGF-binding protein-3 (IGF-BP-3) and thereby reducing its affinity for IGF-I; the addition of prostate-specific antigen to culture medium containing both IGF-I and IGF-BP-3 restored the rate of proliferation of human prostate epithelial cells to that of cells in medium containing only IGF-I.¹⁹⁸

The findings of three retrospective case-control epidemiologic human studies support the hypothesis that increased systemic circulating concentrations of IGF-I increase the risk of developing prostate cancer.^204-206 In an examination of 152 men with prostate cancer and 152 randomly-selected cancer-free men nested within the prospective Physicians’ Health Study, men with plasma IGF-I concentrations greater than 293 ng/ml were at significantly greater risk of developing prostate cancer than were men with plasma IGF-I concentrations less than 185 ng/ml (multivariate-adjusted Relative Risk Ratio (RR): 4.32; 95% confidence interval (CI): 1.76, 10.6; adjusted for height, weight, body mass index, the presence or absence of androgen receptor CAG polymorphisms, and plasma concentrations of IGF-I, IGF-binding protein-3 and prostate-specific antigen).²⁰⁴ Other investigators found that when 52 men with prostate cancer were age-matched to 52 cancer-free men, the risk of developing prostate cancer was significantly correlated with serum IGF-I concentration; every increase in serum IGF-I concentration of 60 ng/ml was accompanied by a doubling of the multivariate-adjusted odds ratio (OR) for the development of prostate cancer (adjusted for age, height, body mass index, years of schooling and serum concentrations of testosterone, estradiol, dihydrotestosterone, dehydroepiandrosterone sulfate and sex hormone-binding protein).²⁰⁵ In another case-control study of 224 men with prostate cancer and 224 age-matched men without cancer, the mean serum IGF-I concentration of men with prostate cancer was significantly greater than that of men without prostate cancer.²⁰⁶ Among the 90 men younger than 70 years of age with prostate cancer and the 84 men younger than 70 years of age without prostate cancer, the risk of developing prostate cancer was significantly correlated with serum IGF-I concentration; every increase in serum IGF-I concentration of 100 ng/ml was accompanied by a tripling of the multivariate-adjusted odds ratio (OR) for the development of prostate cancer (adjusted for age, height and body mass index). This relationship was not statistically significant among the men 70 years of age or older.

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
Lycopene in physiological concentrations has been found to inhibit significantly the rates of proliferation of various human prostate carcinoma cell lines in culture. In concentrations as low as 10-⁸ M, lycopene has been observed to inhibit significantly the proliferation of human LNCaP prostate carcinoma cells in culture.²⁰⁷ In concentrations as low as 10-⁶ M, lycopene has been observed to reduce significantly the viability of cultures of PC-3, DU-145 and LNCaP human prostate carcinoma cells.²⁰⁸ In the presence of 50 x 10-⁶ M alpha-tocopherol, 10-⁶ M lycopene significantly inhibited (by 50% to 90%) the proliferation of PC-3 and DU-145 human prostate carcinoma cells in culture.²⁰⁹

C. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods Containing Lycopene
The hypothesis that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of a randomized placebo-controlled clinical trial^62,210 and an uncontrolled clinical trial,^44,115,211 the findings of five prospective observational studies^212-216 and ten retrospective case-control studies,^{64,67,90,107,114,215-211} a case series²²² and a case report.²²³

In a randomized placebo-controlled clinical trial, men with newly diagnosed localized prostate cancer received daily dietary supplementation (one capsule twice daily) with a commercially available tomato oleoresin extract (Lyc-O-Mato® capsules, LycoRed Natural Products Industries, Beer-Sheva, Israel) containing, per capsule, 14.5 to 15.5 mg of lycopene, 1.45 to 1.55 mg of phytoene, 1.25 to 1.5 mg of phytofluene, 0.25 to 0.5 mg of ß–carotene, 17.25 to 19.25 mg of total mixed carotenoids, 3.75 to 6.25 mg of total tocopherols, 35 to 40 mg of total phospholipids, 1.25 to 1.75 mg of total phytosterols and 182.5 to 190 mg of tomato oil (average total daily supplemental lycopene intake: 30 mg).^62,210 Daily supplementation was begun 3 weeks before the study subjects underwent radical prostatectomy with removal of the entire prostate gland, the seminal vesicles and the surrounding soft tissues. Examination of tissue and blood samples obtained during radical prostatectomy revealed that dietary supplementation with tomato oleoresin extract was associated with significantly less cancerous invasion of surgical margins and extra-prostatic tissues (cancer was confined to the prostate in 73% of the supplemented patients and in only 18% of the unsupplemented men) and significantly less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia, the precursor of prostate cancer^188-194 (cancer was limited to focal involvement in 33% of the supplemented patients but was multifocal and diffuse in all of the unsupplemented men). However, average Gleason tumor score, tumor volume, plasma concentrations of prostate-specific antigen (PSA), IGF-1, IGFBP-3 and total lycopene, malignant prostate tissue content of connexin 43, bcl-2 and bax proteins and total lycopene, benign prostate tissue content of connexin 43, bcl-2 and bax proteins and total lycopene, and peripheral blood lymphocyte 5-OHmdU concentrations were not affected by 3 weeks of daily dietary supplementation with tomato oleoresin extract. The results of this small preliminary study suggest that even short-term dietary supplementation with an amount of tomato oleoresin extract providing the lycopene equivalent of only 4 to 6 fresh tomatoes or 200g of tomato sauce⁵ may effectively interrupt the progression of the precursor lesion, HGPIN, to prostate cancer, even in the absence of statistically significant changes in putative biomarkers of risk for prostate cancer.

In an uncontrolled study, 32 patients (60 to 74 years old) with localized prostate adenocarcinoma (clinical stage T1 or T2) consumed tomato sauce-based pasta dishes containing 200 g of Hunt’s Spaghetti Sauce (Hunt-Wesson, Inc., Irvine, CA) daily for 3 weeks prior to radical prostatectomy.^44,115,211 These foods added an additional 30 mg of lycopene daily to a prescribed diet providing 40% of energy as fat and 15% of energy as protein. Daily consumption of tomato-based foods averaged 81.6% of the intended amount. During the 3 weeks of dietary supplementation, these men experienced significant increases in mean serum total lycopene concentration (96% increase; 95% confidence interval (CI): 42%, 151%; p = 0.0029), mean serum all-trans-lycopene concentration (119% increase; 95% CI: 56%, 183%; p = 0.0019), mean prostate tissue total lycopene content (196% increase; 95% CI: 68%, 323%; p = 0.0071), mean prostate tissue all-trans-lycopene content (310% increase; 95% CI: 92%, 527%; p = 0.0105), mean ratio of all-trans-lycopene to total cis-isomers in prostate tissue (85% increase; 95% CI: 22%, 148%; p = 0.0134) and mean proportion of total lycopene as all-trans-lycopene in prostate tissue (69% increase; 95% CI: 17%, 121%; p = 0.0154). However, the mean ratio of all-trans-lycopene to total cis-isomers in serum and the mean proportion of total lycopene as all-trans-lycopene in serum were not affected by dietary supplementation with tomato sauce. Serum total lycopene concentration and prostate total lycopene content were significantly correlated (r =- 0.51; p = 0.005). In contrast, dietary supplementation with tomato sauce significantly reduced mean serum PSA concentration by 17.5% (p = 0.002) and mean circulating leukocyte 8OHdG concentration by 21.3% (p = 0.005). Prostate tissues obtained at surgery exhibited significantly lower mean 8OHdG content than did an historical control group (28.3% decrease; p = 0.03). Similarly, mean cancer cell 8OHdG staining of Gleason Score-matched resected prostate sections was significantly reduced in mean nuclear density (by an average of 40.5%; p = 0.005) and in mean area (by an average of 36.4%; p = 0.018) compared to tissues obtained via biopsy prior to the study. In contrast, the apoptotic indices of both hyperplastic and neoplastic prostate epithelial cells were significantly increased. These data indicate that the daily consumption of foods containing at least 30 mg of lycopene significantly increased the lycopene contents of blood and prostate tissue, which was accompanied by significant reductions in DNA damage in leukocytes and prostate tissue and significant increases in anticarcinogenic apoptosis among both hyperplastic and neoplastic prostate epithelial cells.^44,115,211

The findings of five prospective observational studies^212-216 have confirmed the beneficial relationship between lycopene consumption (whether as a dietary supplement or consumed as tomatoes or tomato-based foods) and reduced risk for developing prostate cancer. In the 6-year Health Professionals Follow-Up Study, a prospective study of 47,894 men who initially were prostate cancer-free, the daily consumption of more than 6.5 mg of lycopene significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed less than 2.3 mg of lycopene daily (RR: 0.79; 95% CI: 0.64, 0.99; adjusted for age and daily dietary total energy intake).²¹² Similarly, the consumption of tomatoes more than once a week significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed tomatoes an average of one or fewer times a week (RR: 0.74; 95% CI: 0.58, 0.93; adjusted for age and daily dietary total energy intake). The consumption of tomato sauce once weekly significantly reduced the risk for developing prostate cancer, compared to the risk among men who consumed tomato sauce an average of less than once weekly (RR: 0.77; 95% CI: 0.62, 0.95; adjusted for age and daily dietary total energy intake). In contrast, tomato juice consumption appeared in this study to have no effect on the risk for developing prostate cancer.

In a further 6-year extension of the Health Professionals Follow-Up Study, it was determined that the multivariate-adjusted risk for prostate cancer was significantly decreased in men with routine daily lycopene intakes greater than 18.8 mg at the end of the study compared to the risk in men with routine daily lycopene intakes less than 3.4 mg at the end of the study (RR: 0.84; 95% CI: 0.74, 0.96; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid).²¹³ Similarly, the multivariate-adjusted risk for prostate cancer was significantly decreased in men with average estimated cumulative 12-year daily lycopene intakes greater than 18.8 mg compared to the risk in men with average estimated cumulative daily 12-year lycopene intakes less than 3.4 mg (RR: 0.84; 95% CI: 0.73, 0.96; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). However, estimated lycopene intake at the beginning of the study was not associated with risk for prostate cancer. Risk for prostate cancer also was significantly decreased in men consuming two or more servings of tomato sauce (a strong determinant of plasma lycopene concentration⁶⁸) weekly compared to the risk in men consuming less than one serving of tomato sauce monthly, at the beginning of the study (RR: 0.75; 95% CI: 0.64, 0.88; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid), during the 12 years of the study (RR: 0.77; 95% CI: 0.66, 0.90; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid) and at the end of the study (RR: 0.84; 95% CI: 0.72, 0.99; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). The prostate cancer-preventing properties of two or more weekly servings of tomato sauce were evident in men of Southern European ancestry (RR: 0.66; 95% CI: 0.47, 0.93; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid) and men of other Caucasian ancestry (RR: 0.79; 95% CI: 0.65, 0.98; adjusted for age, study time period, ancestry, body mass index at age 21 years and dietary daily intakes of total energy, calcium, phosphorus, fructose, vitamin D, vitamin E, total fat and a–linolenic acid). The prostate cancer-preventing properties of two or more weekly servings of tomato sauce remained statistically significant when additionally adjusted for olive oil preference (RR: 0.77; 95% CI: 0.66, 0.91) or fruit and vegetable intake (RR: 0.78; 95% CI: 0.66, 0.91).

These investigators detected no evidence that “detection bias,” changes in the relative frequency of diagnosis of prostate cancer during the study that might result from advances in diagnostic and screening practices and technologies that may have occurred during the 12 years of the study, influenced the evidence that the consumption of the highest quintile of lycopene intake, and in particular, of two or more servings of tomato sauce weekly, significantly reduced the risk of developing prostate cancer.

In another prospective study, dietary and lifestyle characteristics were evaluated in relation to subsequent prostatic cancer risk in approximately 14,000 Seventh-day Adventist men who were observed for 6 years (some 78,000 man-years of observation).²¹⁴ Among these men, the consumption of one or more tomatoes weekly significantly decreased their age-adjusted risk for prostate cancer, compared to the risk among men who consumed tomatoes less than once a week (RR: 0.62; 95% CI: 0.40, 0.96). This reduction in relative risk was not affected by age, education, or intakes during the sixth year of the study of meat, poultry, fish, beans, legumes, peas, citrus fruit, dry fruit or nuts.

In a 5- to 8-year prospective observational study of 1,575 cancer-free men aged 40 to 86 years at the beginning of the study, the risk for developing prostate cancer was significantly reduced among the men with the highest tertile of daily dietary lycopene intake, compared to the risk among men with the lowest tertile of daily dietary lycopene intake (RR: 0.5; 95% CI: 0.3, 0.9; adjusted for age and dietary daily total energy intake).²¹⁵ The reduction in risk for the development of advanced prostate cancer reportedly was even greater (data not given).

In an ecologic epidemiologic study of diet and prostate cancer worldwide it was found that, in 28 those countries where tomatoes were consumed regularly, mortality from prostate cancer was significantly inversely correlated with tomato intake.²¹⁶

The findings of four retrospective case-control studies^217-220 also support the conclusion that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based products containing lycopene. In a study of 223 men with prostate cancer and 446 matched cancer-free men, the consumption of tomatoes or tomato-based products 14 or more times a month significantly reduced the risk for developing prostate cancer, compared to the risk among men consuming tomatoes or tomato-based products less than 3 times monthly (odds ratio (OR): 0.71; significantly different from OR = 1.0, p < 0.05).²¹⁷ Similarly, in a study of 320 men with prostate cancer and 246 cancer-free men, the consumption of cooked tomatoes at least 4 times weekly significantly reduced the risk for the development of prostate cancer, compared to the risk among men who consumed cooked tomatoes twice weekly (OR: 0.85; 95% CI: 0.75, 0.97; adjusted for age, height, education and daily dietary total energy intake).²¹⁸

In a study of 617 men with prostate cancer and 636 men without prostate cancer, daily consumption of more than 110 g of tomatoes significantly reduced the risk for developing prostate cancer, compared to the risk for men consuming less than 9 g of tomatoes daily (OR: 0.64; 95% CI: 0.45, 0.91; adjusted for vasectomy status, age, cigarette smoking status, marital status, study area, body mass index, education, current or recent use of multivitamin dietary supplements, and dietary intakes of total energy, grains, fruit, vegetables, all plants, all carotenoids, folate and folic acid, dietary fiber, conjugated linoleic acid, vitamin E, vitamin C, retinol, total fat and linoleic acid).²¹⁹ Among these men, lycopene intake was not associated with the multivariate –adjusted risk for developing prostate cancer, even though 25% of these men consumed over 12.7 mg of lycopene daily. However, in a study of 77 men with prostate cancer and 183 cancer-free men, the median daily lycopene intake of the men with prostate cancer (0.817 mg) was significantly less than the median daily lycopene intake of the men without prostate cancer (1.120 mg).²²⁰

The findings of six retrospective case-control studies^{64,67,90,107,114,221} support the conclusion that the risk for developing prostate cancer is reduced among those men with the greatest serum or plasma total lycopene concentrations (reflecting the greatest routine lycopene intakes). This conclusion is consistent with and provides additional support for the conclusion that the risk for developing prostate cancer is reduced by consumption of either supplemental lycopene or of tomatoes and tomato-based products containing lycopene.

A prospective case-control study, nested within the randomized placebo-controlled Physicians' Health Study of aspirin and ß-carotene, compared 578 men who developed prostate cancer during 13 years of the study to 1294 age- and smoking status-matched men who did not develop prostate cancer during 13 years of the study.¹¹⁴ Pre-study median plasma total lycopene concentration was significantly lower in the men who later developed prostate cancer (0.69 x 10-⁶ M) than it was in the men who remained prostate cancer-free (0.72 x 10-⁶ M). Although the risk for developing any type of prostate cancer was not affected by pre-study plasma total lycopene concentrations (OR: 0.75; 95% CI: 0.54, 1.06; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration), the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.56; 95% CI: 0.34, 0.91; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). In the men whose diets were supplemented with placebo but not with aspirin or ß-carotene, the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.40; 95% CI: 0.19, 0.84; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). Similarly, in the men whose diets were supplemented with ß-carotene but not with aspirin or placebo, the risk for developing aggressive prostate cancer was significantly decreased in men with pre-study plasma total lycopene concentrations greater than 1.1 x 10-⁶ M, compared to the risk for developing aggressive prostate cancer in men with pre-study plasma total lycopene concentrations less than 0.5 x 10-⁶ M (OR: 0.48; 95% CI: 0.24, 0.94; adjusted for exercise frequency, body mass index, alcohol consumption, use of multivitamin dietary supplements and plasma total cholesterol concentration). These reductions in the risks for developing aggressive prostate cancer were not affected by age, smoking status, body mass index, exercise level, alcohol consumption, multivitamin dietary supplementation, or plasma total cholesterol concentration and suggest that lycopene may differentially impair the development of more aggressive, invasive and diffuse forms of prostate cancer.

In a case-control study of 65 men with prostate cancer and 132 matched cancer-free men, mean plasma total lycopene concentration was significantly lower among the men with prostate cancer (0.22 x 10-⁶ M) than among the men without cancer (0.31 x 10-⁶ M).64 Among all 197 men, the risk for developing prostate cancer among those men with plasma total lycopene concentrations greater than 0.40 x 10-⁶ M was significantly lower than the risk among those men with plasma total lycopene concentrations lower than 0.18 x 10-⁶ M (OR: 0.17; 95% CI: 0.04, 0.78; adjusted for age, race, years of education, daily total caloric intake, number of pack-years of cigarette smoking, alcohol consumption and family history of prostate cancer). This significant risk reduction was readily apparent among men younger than 60 years (multivariate-adjusted OR: 0.05; 95% CI: 0.01, 0.51) but was not apparent among men 60 years of age or older (multivariate-adjusted OR: 0.10; 95% CI: 0.01, 3.31). However, estimated lycopene intake was not associated with multivariate-adjusted risk for developing prostate cancer in this study, with only 25% of these men consuming more than 3.5 mg of lycopene daily.

In a retrospective case-control study of 12 men with prostate cancer and 12 cancer-free men, mean serum total lycopene concentration was significantly lower among the men with prostate cancer (0.24 x 10-⁶ M) than among the cancer-free men (0.43 x 10-⁶ M).⁹⁰ .In addition, mean prostate tissue total lycopene content also was significantly lower among the men with prostate cancer. Similarly, in a study of 24 men with prostate cancer and 18 men without prostate cancer but undergoing surgical transurethral resection or radical cystoprostatectomy, mean serum total lycopene concentration was significantly lower among the men with prostate cancer than among cancer-free men (data not shown).²²¹ In addition, mean total lycopene contents of benign prostate tissue were significantly lower among the men with prostate cancer.

In a study of 209 men with prostate cancer and 228 cancer-free men, serum total lycopene concentrations greater than 0.46 x 10-⁶ M were associated with significantly reduced risk for the development of aggressive prostate cancer, compared to the risk of men with serum total lycopene concentrations less than 0.20 x 10-⁶ M (OR: 0.37; 95% CI: 0.15, 0.94; adjusted for age, race, study center and month of blood sampling).107 In contrast, serum total lycopene concentration was not associated with multivariate-adjusted risk for developing nonaggressive prostate cancer and the median serum total lycopene concentrations were not different among the men with or without prostate cancer (African Americans without cancer: 0.29 x 10-⁶ M; African Americans with prostate cancer: 0.27 x 10-⁶ M; Caucasian Americans without cancer: 0.35 x 10-⁶ M; Caucasian Americans with prostate cancer: 0.31 x 10-⁶ M).

In another case-control study of 15 men with prostate cancer and 30 cancer-free men, the median plasma total lycopene concentration of men with prostate cancer (0.12 x 10-⁶ M) was significantly lower than that of men without cancer (0.34 x 10-⁶ M).⁶⁷

The findings of an analysis of a series of 112 men without cancer suggest that daily consumption of one serving of cooked tomatoes significantly decreased serum IGF-I concentration by 31.5%.222

A case report supports the conclusion that the risk of developing prostate cancer is reduced by consumption of supplemental lycopene. In this case, a man with androgen-independent pharmacologically-refractive terminal prostate cancer experienced remission within one month of beginning daily dietary supplementation with a combination of 30 mg of lycopene and 900 mg of saw palmetto extract.²²³ At the time of submission of this report, the individual had been in continuing remission (with continued daily dietary supplementation) for 18 months.

Several retrospective epidemiologic case-control observational studies have failed to observe the beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk for developing prostate cancer.^224-232 In these studies, lycopene intake or the consumption of tomatoes or tomato-based foods was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing prostate cancer was predictable.

In one such study of 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched cancer-free men, no statistically significant relationships were observed between the daily consumption of lycopene, raw tomatoes or cooked tomatoes and risks for developing prostate cancer (adjusted for social class).²²⁴ However, fewer than 25% of these men consumed at least 0.7 mg of lycopene (amount of lycopene in one-half teaspoon of catsup⁵) daily, fewer than 20% consumed at least 1 serving of raw tomatoes daily and fewer than 20% consumed at least 2 servings of cooked tomato products weekly.

In a study of men 40 to 64 years of age, 628 newly diagnosed with aggressive prostate cancer and 602 who were free of cancer, no statistically significant relationships were observed between the daily consumption of lycopene, raw tomatoes or cooked tomatoes and risks for developing prostate cancer.²²⁵ However, only half of these men routinely consumed over 2 mg of lycopene (less than the amount of lycopene in a level tablespoon of catsup⁵) daily, only 25% consumed at least 10 mg of lycopene daily and fewer than 30% consumed more than an average of one-half of a serving of cooked or raw tomato products daily.

In a retrospective case-control study of 449 African-American men and 483 Caucasian men with prostate cancer and 543 African-American men and 658 Caucasian cancer-free men, the rates of daily consumption of raw tomatoes, cooked tomatoes or tomato sauces, tomato juice, watermelon or these foods combined were not associated with the risks (adjusted for age, study site, daily caloric intake, and race) for developing either early or advanced prostate cancer among African-American men, Caucasian men or both groups of men combined.²²⁶ However, only 25% of these men consumed at least one serving of any of these foods daily.

In a case-control study nested within a 6-year prospective observational study of 58,279 initially cancer-freemen aged 55 to 69 years at the beginning of the study, daily lycopene intake was not associated with the risk for developing any degree of prostate cancer (adjusted for age, family history of prostate cancer, socioeconomic status and alcohol consumption) among 642 men who developed prostate cancer and 1525 men who did not.²²⁷However, among both groups of men, mean daily lycopene intake was estimated to be 1 mg (less than the amount of lycopene in a level teaspoon of catsup⁵) and fewer than 3% of the men who developed prostate cancer consumed more than 3.4 mg of lycopene daily and fewer than 3% of the men who did not develop prostate cancer routinely consumed more than 2.6 mg of lycopene daily.

In a case-control study of 317 men with prostate cancer and 480 matched cancer-free men, daily lycopene intake, raw tomato consumption and consumption of cooked foods containing tomatoes were not associated with the risks for developing prostate cancer (adjusted for age, height, use of nonsteroidal anti-inflammatory medications and socioeconomic status).²²⁸ However, only 25% of these men consumed more than 35 g (equivalent to one-quarter serving5) of raw tomatoes daily, more than 64 g (including water) of cooked foods containing tomatoes or more than 2 mg of lycopene from all sources daily.

In a study of 610 men with prostate cancer and 456 cancer-free men, daily mean tomato and tomato juice intakes did not differ between those with prostate cancer and those without.²²⁹ Tomato and tomato juice consumption were without effect on the risk for prostate cancer (adjusted for age, family history of prostate cancer, socioeconomic status, fruit consumption and vegetable consumption). Among these men, less than 3% consumed more than 60 g of tomatoes and tomato juice combined daily.

In a study of 1619 men with prostate cancer and 1618 cancer-free men, the daily intakes of either all tomato products or of cooked tomato products only were not associated with the risks for developing any prostate cancer or advanced prostate cancer (adjusted for age, education, ethnicity, geographic area of residence and daily total caloric intake).²³⁰ However, only 20% of these men consumed over 108 g of total tomato products (equivalent to three-quarters of one serving⁵) daily. The results were similar when the men were subgrouped by ethnicity (African-Americans, Caucasian-Americans, Chinese-Americans, Japanese-Americans).

In a re-analysis of previously-published data from a retrospective case-control study of 452 prostate cancer cases and 899 cancer-free individuals that was conducted between 1970 and 1983 among the multiethnic population of Hawaii, investigators reported failure to discover a statistically significant relationship between the consumption of tomatoes and the risk for developing prostate cancer.²³¹ The percentage of these men who consumed at least 1 mg of lycopene or 1 tomato daily could not be determined from the data provided. In another case-control study in which daily lycopene intakes cannot be determined, daily lycopene intakes of 215 men with prostate cancer and 593 matched cancer-free men were not associated with risk for developing prostate cancer (adjusted for age, education, family history of prostate cancer and total daily energy intake).²³²

In four retrospective case-control studies, the risk for developing prostate cancer was not observed to be associated with serum or plasma total lycopene concentrations.^{54,75,233,234} In one such study, nested within a 13-year prospective epidemiologic observational study, no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer (OR comparing the highest quartile of serum total lycopene concentration with the lowest quartile of serum total lycopene concentration (0.50) was not different from 1.0; 95% CI: 0.20, 1.29).²³³ However, the 75th percentile of serum total lycopene concentration was only 45 mcg/dL, a concentration only 65% of the mean serum total lycopene concentration achieved with daily dietary supplementation with 30 mg of lycopene in a prospective intervention study (and therefore only 65% of the serum total lycopene concentration achieved by about half of the men that received daily dietary supplementation with 30 mg of lycopene in a prospective intervention study).²¹¹

In a retrospective case-control study of 182 men with prostate cancer and 364 matched cancer-free men (the “CLUE I” study), median serum total lycopene concentrations were not different between men with (0.64 x 10-⁶ M) and without prostate cancer (0.66 x 10-⁶ M) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁵⁴ In a similar study of 142 men with prostate cancer and 284 matched cancer-free men (the “CLUE II” study), median serum total lycopene concentrations were not different between men with (0.72 x 10-⁶ M) and without prostate cancer (0.78 x 10-⁶ M) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁵⁴

In a retrospective case-control study of 142 men with prostate cancer and 142 matched cancer-free men, median serum total lycopene concentrations were not different between men with and without prostate cancer (0.25 x 10-⁶ M in both groups) and no statistically significant relationship was observed between serum total lycopene concentration and the risk for developing prostate cancer.⁷⁵ In another retrospective case-control study of 103 men with prostate cancer and 103 cancer-free men, serum total lycopene concentration was not observed to be associated with the risk for developing prostate cancer.²³⁴

D. The Available Evidence Provides Significant Scientific Support for the Conclusion that Risk for Developing Prostate Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The results of the only relevant randomized placebo-controlled clinical trial,²¹⁰ the only relevant uncontrolled clinical trial^44,115,211 and all of the published prospective observational studies^212-216 consistently demonstrate a beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk for developing prostate cancer. This compelling evidence of risk reduction is strengthened by the findings of ten retrospective case-control studies^{64,67,90,107,114,217-221} and by a case series²²² and case report.²²³ Other reviewers have concluded that “Several case-control and prospective cohort studies focusing on dietary assessment suggest that the consumption of tomato and tomato products may be associated with a lower risk of prostate cancer.”235 In addition, “Food processing or cooking of tomatoes does not seem to reduce the benefits and may in fact provide greater advantage by improving the bioavailability of beneficial components.”²³⁵

Although there have been reports of retrospective case-control studies that have failed to observe this protective effect,^{54,75,224-234} these reports likely reflect failure of study subjects to consume lycopene, tomatoes or tomato-based foods, as well as confounding by related factors and heterogeneity of effect (this can occur when a subpopulation of nonresponders dilutes the overall effect of a chemopreventive agent or food and obscures the association in responders), resulting in underestimation of the effects of the nutrient or food of interest on chemoprevention.²³⁶ Furthermore, no report has claimed that an increase in the risk for developing prostate cancer was associated with the consumption of lycopene, tomatoes or tomato-based foods.

The published scientific evidence strongly supports the conclusion that the risk of developing prostate cancer is reduced by dietary supplementation with lycopene and by the consumption of tomatoes and tomato-based products containing lycopene.

V. Lung Cancer

Lung cancer is the second leading cause of newly-diagnosed cancer in males and females in the US.¹⁵⁹ About 171,900 new cases of lung cancer were forecast for the US for the year 2003, while nearly 89,000 men and 69,000 women in the US were expected to die from this disease that year (accounting for about 28% of all cancer-related deaths).¹⁵⁹ The 1-year relative survival rate for individuals diagnosed with lung cancer is 42% and the 5-year relative survival rate for all lung cancers combined is 15%, although the 5-year relative survival rate is 49% when the disease is localized when detected.¹⁵⁹

A. Pathogenesis of Lung Cancer
Carcinogenesis in the lung occurs in a multistage process involving a series of genetic alterations with progression through a variety of pathways from initial reversible lesions to the development of metastatic disease.²³⁷ The initial triggers of carcinogenic change may be varied as may be the factors that provide the impetus for continued disease progression. For example, reactive oxygen species (such as the hydroxyl radical OH? ) may be implicated in the pathogenesis of lung cancer.²³⁷ Exposure of the lung to ozone produces oxidative damage similar to that of the lesions observed in precancerous change in the lungs.^237,238 Experimental ozone exposure of the human lung to ozone in vivo produces oxidative damage and an increase in the frequency of single-stand DNA damage in lung epithelial cells.^239,240

The insulin-like growth factors (IGF-I and IGF-II) are circulating mitogens that interact with target cells via the cell membrane-bound IGF-receptor to influence the regulation of cell proliferation, differentiation, apoptosis and neoplastic transformation.^195,196 In particular, IGF-I is a potent mitogen that stimulates DNA synthesis and the progression of the cell cycle from the G1 phase to the S phase while also stimulating the expression of proapoptotic Bcl proteins and suppressing the expression of antiapoptotic Bax proteins.¹⁹⁷ There is evidence that the risk of neoplastic transformation within a cell population increases as the proliferation rate of cells within the population increases,^200,201 suggesting that IGF-I availability to IGF-I-responsive tissues contributes to risk of developing tissue-specific cancer.¹⁹⁹ Furthermore, increased IGF-I availability may accelerate the proliferation and clonal expansion of epithelial undergoing the process of neoplastic transformation.¹⁹⁹ The results of a retrospective case-control study support the hypothesis that IGF-I is associated with lung cancer.²⁴¹ In that study, individuals with the highest quartile of plasma IGF-I concentrations were at significantly increased risk of developing lung cancer, compared to the risk among subjects with the lowest quartile of plasma IGF-I concentrations (OR: 2.75; 95% CI: 1.37, 5.53; adjusted for plasma IGF-BP-3 concentration).

B. Cell Culture Studies Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The addition of physiological concentrations of lycopene (1 to 2 x 10-⁶ M) to cultures of NCI-H226 human lung cancer cells significantly inhibited both basal and IGF-I-stimulated rates of DNA synthesis and cell proliferation.²⁴²

C. Animal Studies Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing lung cancer is reduced by consumption of supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of studies in experimental animals. Ferrets exposed to cigarette smoke for 9 weeks developed accelerated epithelial cell proliferation and squamous metaplasia of the lungs which were significantly inhibited by concurrent dietary supplementation with lycopene in amounts equivalent to human intakes of 15mg or 60 mg daily.²⁴³ In addition, both levels of dietary supplementation with lycopene prevented cigarette smoke-induced deactivation of the apoptosis-promoting Bcl-2 proteins. In mice, dietary supplementation with lycopene during the postinitiation stage of lung carcinogenesis significantly reduced the extent of lung neoplasia induced by combined pretreatment with diethylnitrosamine plus N-methyl-N-nitrosourea plus 1,2-dimethyl hydrazine HCl.²⁴⁴

D. Human Clinical Trials Provide Scientific Support for the Conclusion that Risk of Developing Lung Cancer is Reduced by the Consumption of Lycopene, Tomatoes or Tomato-Based Foods
The hypothesis that the risk for developing lung cancer is reduced by consumption of supplemental lycopene or of tomatoes and tomato-based foods containing lycopene is supported by the results of the findings of two prospective observational studies,^68,245,246 a retrospective cohort study²⁴⁷ and five retrospective case-control studies.^248-252

The findings of two prospective observational studies^245,246 have confirmed the beneficial relationship between lycopene consumption (whether as a dietary supplement or consumed as tomatoes or tomato-based foods) and reduced risk for developing lung cancer. When data from the 10-year prospective Health Professionals Follow-Up Study of 46,924 men and the 12-year prospective Nurses’ Health Study of 77,283 women were combined, the men and women with a median daily lycopene intake of 14.7 mg experienced a significantly reduced risk for the development of lung cancer, compared to the risk experienced by men and women with a median daily lycopene intake of 4.4 mg (RR: 0.80; 95% CI: 0.64, 0.99; adjusted for age, smoking status, age when cigarette smoking began, daily dietary total caloric intake and whether the subject joined a study during years 1-4, 5-8 or 9-12).^68,246 Interestingly, the chemopreventive effect of lycopene was not evident among the men and women who either never smoked cigarettes or who had quit smoking prior to or during the study, while men and women who were continuing to smoke at the end of the study with a median daily lycopene intake of 14.7 mg experienced a significantly reduced risk for the development of lung cancer, compared to the risk experienced by men and women who were continuing to smoke at the end of the study with a median daily lycopene intake of 4.4 mg (RR: 0.63; 95% CI: 0.45, 0.88; adjusted for age, age when cigarette smoking began, severity of cigarette smoking at the end of the study, daily dietary total caloric intake and whether the subject joined a study during years 1-4, 5-8 or 9-12).

In a re-analysis of the data obtained during the prospective Alpha-Tocopherol, Beta-Carotene Cohort Study of 27,084 male smokers who completed a 276-food item dietary questionnaire when they each joined the cohort, it was reported that daily intake of lycopene in excess of 1.17 mg significantly reduced the risk for the development of lung cancer, compared to the risk among men who consumed less than 0.23 mg of lycopene daily (RR: 0.72; 95% CI: 0.61, 0.84; adjusted for age, years of cigarette smoking, number of cigarettes smoked daily, whether supplemented with alpha-tocopherol or ß-carotene, whether dietary supplements containing ß-carotene or vitamin A were consumed, and dietary daily intakes of total energy, total fat and cholesterol).²⁴⁵

On the island of Oahu, Hawai’i, among a cohort of 463 men and 212 women with lung cancer, the daily consumption of more than 50 g of tomatoes or tomato-based foods by men with lung cancer significantly reduced the risk of death from lung cancer, compared to the risk among men with lung cancer who consumed less than 6.5 g of tomatoes or tomato-based foods daily (RR: 0.77; significantly different from RR = 1.0, p < 0.05; adjusted for age at diagnosis, stage of lung cancer, histologic appearance of lung cancer and body mass index).²⁴⁷ Among the cohort of women with lung cancer, the daily consumption of more than 42 g of tomatoes or tomato-based foods significantly reduced the risk of death from lung cancer, compared to the risk among women with lung cancer who consumed less than 6.5 g of tomatoes or tomato-based foods daily (RR: 0.50; significantly different from RR = 1.0, p < 0.05; adjusted for age at diagnosis, stage of lung cancer, histologic appearance of lung cancer and body mass index). However, attempts to determine whether this beneficial effect of tomato consumption was specific to specific types of lung cancer (i.e., adenocarcinoma, small cell cancer or squamous cell cancer) were unsuccessful.

The findings of five retrospective case-control studies^248-252 also support the conclusion that the risk for developing lung cancer is reduced by consumption of tomatoes and tomato-based foods and of lycopene. In a study of 230 men and 102 women with lung cancer and 597 men and 268 women who were cancer-free, those subjects with the highest quartile of consumption of tomatoes or tomato-based foods experienced significantly lower risk for developing lung cancer than did those subjects with the lowest quartile of consumption of tomatoes or tomato-based foods (men: OR: 0.43; significantly different from RR = 1.0, p < 0.05; women: OR: 0.27; significantly different from RR = 1.0, p < 0.05; adjusted for age, ethnicity, smoking status, number of pack-years of cigarette smoking and dietary daily cholesterol intake).²⁴⁸ However, among this subject population, despite the chemopreventive effect of tomato consumption, estimated lycopene intake was not associated with reduced risk for developing lung cancer.²⁵³

In another retrospective case-control study of 402 men and 104 women with lung cancer and 741 men and 304 women who were cancer-free, tomato consumption again was protective against the development of lung cancer.²⁴⁹ Men and women who consumed one or more servings of tomatoes daily experienced significantly lower risk for developing adenocarcinoma of the lung than did men and women who consumed only one serving per week (OR: 0.5; 95% CI: 0.4, 0.6; adjusted for age, sex and study center). However, tomato consumption did not appear to affect the risk for developing either small cell carcinoma or squamous cell carcinoma of the lung.

Among another sample of women, 103 with lung cancer and 206 without, although mean tomato intake was not different between those with and those without cancer, the risk of developing lung cancer was significantly altered by tomato intake.²⁵⁰ Women with the highest tertile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did women with the lowest tertile of daily tomato intake (OR: 0.45; 95% CI: 0.22, 0.91; adjusted for smoking status of number of pack-years of cigarette smoking). Although the risk for adenocarcinoma of the lung among all 306 women was not affected by tomato intake, among the 230 women who had never smoked cigarettes, those with the highest tertile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did women with the lowest tertile of daily tomato intake (unadjusted OR: 0.38; 95% CI: 0.17, 0.83).

Similarly, among 183 men with lung cancer and 183 cancer-free men, men with the highest quartile of daily tomato intake experienced a significantly lower risk of developing any lung cancer than did men with the lowest quartile of daily tomato intake (OR: 0.42; 95% CI: 0.25, 0.99; adjusted for lifetime exposure to tobacco, age at time of diagnosis of lung cancer, height, number of meals usually eaten at home daily, income, education and occupation).²⁵¹ In addition, the mean daily tomato intake of the men without lung cancer was significantly greater than that of the men with lung cancer.

The influence of plasma lycopene concentration on the risk of developing lung cancer was examined in 93 subjects with non-small cell lung cancer and 102 cancer-free men and women.²⁵² Among these individuals, mean plasma total lycopene concentration was significantly greater among the men and women without lung cancer. In addition, subjects with the highest tertile of plasma total lycopene concentrations had significantly reduced risk for developing any non-small cell form of lung cancer than had subjects with the lowest tertile of plasma total lycopene concentrations (OR: 0.37; significantly different from OR = 1.0, p < 0.05; adjusted for age, sex and race). Among African-Americans with the highest tertile of plasma total lycopene concentrations, the risk for developing any non-small cell form of lung cancer was even lower (OR: 0.12; significantly different from OR = 1.0, p < 0.05; adjusted for age and sex). In addition, among all subjects, those with the highest tertile of plasma total lycopene concentrations had significantly reduced risk for developing squamous cell lung cancer, compared to the risk of subjects with the lowest tertile of plasma total lycopene concentrations (OR: 0.25; significantly different from OR = 1.0, p < 0.05; adjusted for age, sex and race).

The results of several prospective observational studies have failed to demonstrate the beneficial protective effect of the consumption of lycopene, tomatoes and tomato-based foods on the risk of developing lung cancer.^254-258 In most of these studies, lycopene intake or the consumption of tomatoes or tomato-based foods was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing lung cancer was predictable.^254-257

For example, in the 6-year prospective Netherlands Cohort Study on Diet and Cancer, daily lycopene intake appeared to have no effect on the multivariate-risk of developing any lung cancer, small cell carcinoma of the lung, squamous cell carcinoma of the lung or adenocarcinoma of the lung in 58,279 men.²⁵⁴ However, fewer than 5% of these men consumed more than 4 mg of lycopene (equivalent to 1.5 level tablespoons of catsup⁵) daily. Similarly, in a prospective observational study of 4,545 men, daily lycopene intake appeared to have no effect on the age- and smoking status-adjusted risk of developing any lung cancer; less than 30% of these men consumed more than 1 mg of lycopene daily.²⁵⁵ In another, 11.5-year prospective study of 13,785 men and 2,928 women, of whom only 5% consumed at one-half of a serving of tomatoes daily, tomato consumption was not related to risk for developing lung cancer.²⁵⁶ In a much larger prospective 16-year study of 121,700 women in the U.S. (the Nurses’ Health Study), neither tomato consumption nor lycopene intake were significantly related to the incidence of lung cancer; however, the lycopene consumption by these subjects cannot be determined.²⁵⁷ However, the results of a large 6-year prospective study of 34,198 California Seventh-Day Adventists, one-third of whom consumed at least one serving of tomatoes daily, failed to demonstrate a significantly protective effect of tomato consumption on risk of developing lung cancer.²⁵⁸

The investigators of a number of retrospective case-control studies have failed to observe significant risk-reducing relationships between tomato consumption and lung cancer or between lycopene intake and lung cancer.^{45,59,253,259-271} However, in most of these studies, the consumption of tomatoes or lycopene was minimal or absent in a large percentage of the study subjects and failure to observe the beneficial protective effect of the consumption of dietary ingredients that were not consumed on the risk for developing lung cancer was predictable.^{45,59,253,259-268}

In one retrospective case-control study of 230 men and 102 women with lung cancer and 597 men and 268 women who were cancer-free, lycopene intake did not affect the multivariate-risk of developing lung cancer by either the men or the women.²⁵³ However, 75% of the men consumed less than 4.2 mg of lycopene daily and 75% of the women consumed less than 3.6 mg of lycopene (equivalent to 1.5 level tablespoons of catsup⁵) daily. Similarly, although lycopene intake did not affect the risk of developing lung cancer among 103 women with lung cancer and 206 women without lung cancer, fewer than 25% of these women consumed more than 2 mg of lycopene daily.²⁵⁹ In another sample of 541 men with lung cancer and 540 matched cancer-free men, although lycopene intake did not affect the risk of developing lung cancer, fewer than 25% of these men consumed more than 2 mg of lycopene daily.²⁶⁰ In another retrospective case-control study (nested within a much larger prospective study) in which the mean lycopene intake of men with lung cancer was no different from the mean intake of men without lung cancer, less than 3% of the 4,538 subjects consumed more than 2.5 mg of lycopene (the amount of lycopene in one level tablespoon of cats