Download Lycopene and prostate cancer

Prostate Cancer and Prostatic Diseases (2002) 5, 6–12
ß 2002 Nature Publishing Group All rights reserved 1365–7852/02 $25.00
www.nature.com/pcan
Review
Lycopene and prostate cancer
NJ Barber1* & J Barber2
1Department of Urology, St George’s Hospital, London, UK; and 2Department of Biological
Sciences, Imperial College, London, UK
The role of diet and dietary supplements in the development and progression of
prostate cancer represents an increasingly frequent topic of discussion in the
urologist’s office. As access to information becomes forever easier, patients are
more aware and educated about this subject than ever before. The role of
antioxidants including carotenoids in all this has been the subject of great
interest for some time. Lycopene, the carotenoid that gives tomatoes and other
fruits and vegetables their red colour, has been of particular interest recently as
regards its role in prostate cancer. The aim of this review is to briefly outline the
biology and chemistry of lycopene, the scientific basis for its proposed anticancer
properties and evaluate what conclusions the practicing urologist may draw from
the data thus far. The media and industry have raced to encourage not only diets
high in lycopene but also dietary lycopene supplements but there is probably
only sufficient evidence to recommend to patients a diet rich in all vegetables and
fruits of which tomatoes and tomato based products should certainly be a part.
Prostate Cancer and Prostatic Diseases (2002) 5, 6–12. DOI: 10.1038/sj/pcan/4500560
Keywords: carotenoids; lycopene; prostate cancer
Introduction
In the twenty first century the public are increasingly
more educated regarding health issues. With this comes a
greater awareness of the incidence of prostate cancer in
the population and inevitably, therefore, more interest in
what lifestyle changes may help in the avoidance of this
common disease. The incidence and mortality rates of
prostate cancer vary geographically but are strongly
associated with affluence and dietary factors related to
affluence.1,2 Populations who migrate from low risk
countries, for example Japan and Poland to the USA,
suffer an increase risk of developing the disease.3,4
Furthermore, as previously low risk countries have
become more westernized so the incidence of prostate
cancer has risen.2 Around the world and particularly in
the USA this has led to numerous epidemiological studies
investigating the link between diet and all cancers including that of the prostate gland. To date a long list of dietary
factors have been associated with the development of
*Correspondence: NJ Barber, Department of Urology, St George’s
Hospital, Blackshaw Road, London SW17 0QT, UK.
Received 24 July 2001; revised 8 October 2001; accepted
1 November 2001
prostate cancer including fat, specific fatty acids, soy,
calcium, various vegetables, lycopene and supplements
of vitamin E, selenium, vitamin C and zinc. It was
analysis of data from the Health Professionals FollowUp (HPFU) study that first indicated a possible inverse
relationship between the intake of lycopene and the risk
of prostate cancer.5 Not surprisingly, this has led to a great
deal of enthusiasm for the recommendation of lycopene
containing foodstuffs as a regular part of a healthy diet.
Indeed, Heinz, for example, have established an intensive
advertising campaign to promote their lycopene-rich
products (Figure 1). There are now even numerous websites expounding the benefits of dietary lycopene, eg
lycopene.com, lycopene — advice.com, lycopene.org,
lycored.com and tomatolycopene.com and even more
advertising lycopene containing dietary supplements.
Famously the departing Mayor of New York, Rudolph
Giuliani, has also declared that he now eats large
amounts of lycopene-rich plum tomatoes having been
diagnosed with prostate cancer.
In this review we hope to briefly outline the nature of
lycopene, the scientific basis for its proposed anti cancer
properties and discuss the evidence thus far as related to
its role in the incidence of prostate cancer such that
urologists may be better armed in the face of ever more
knowledgeable and inquiring patients.
Lycopene and prostate cancer
NJ Barber and J Barber
Table 1 The lycopene content of common foods (24)
Food
Fresh tomatoes
Cooked tomatoes
Tomato sauce
Tomato paste
Condensed tomato soup
Tomato powder
Tomato juice
Sun-dried tomato in oil
Canned pizza sauce
Ketchup
Apricot
Canned apricot
Dried apricot
Pink grapefruit
Guava
Guava juice
Watermelon
Papaya
7
Content (mg/100 g)
0.88 – 4.20
3.70
6.20
5.40 – 150.00
7.99
112.63 – 126.49
5.00 – 11.60
46.50
12.71
9.90 – 13.44
< 0.01
0.06
0.86
3.36
5.40
3.34
2.30 – 7.20
2.00 – 5.30
Figure 1 Front page of a booklet produced by HJ Heinz Co. Ltd as a
promotion for the potential health giving properties of lycopene through
consumption of their tomato based products. In the UK this company is
now stating on their tomato ketchup bottles a lycopene content of ‘2 mg
lycopene per 10 ml serving’.
The chemistry and biology of lycopene
Lycopene is a member of a group of natural pigments
known as carotenoids. Carotenoids are synthesized by
both plants and micro-organisms and are widely found in
the environment, giving, for example, the colours to many
flowers, fruits and vegetables. Animals cannot synthesize
carotenoids and rely on ingestion for their source of these
molecules. In plants the principal function of this family is
to serve as light absorbing pigments and also protect cells
against photo-oxidative damage during the process of
photosynthesis. For humans, carotenoids have a dietary
role; principally that of beta-carotene, which serves as a
source of vitamin A. Until recently less emphasis has been
placed on the importance of lycopene as a dietary factor.
While beta-carotene is orange and responsible for the
colour of carrots for example, lycopene gives the red
colour to tomatoes and other fruits such as guava, watermelon, pink grapefruit and papaya (see Table 1). In the
Western world 85% or more of dietary lycopene comes
from tomatoes and tomato based products. In the UK the
average intake is about 1 mg which is lower than that
estimated for the USA by about five times.
Thus far, more than 600 carotenoids have been
described and as a family they share common structural
features. These include a number of centrally located
conjugated double bonds and a polyisoprenoid structure.
Lycopene itself is an acrylic and extremely hydrophobic
carotenoid and is known to have 13 conjugated double
Figure 2 Structure of all trans-lycopene and some of its cis-isomers.
bonds arranged in a linear fashion (Figure 2). It is a lack of
a beta ionone ring that leaves lycopene free of provitamin
A activity. The conjugated double bonds allow lycopene
and indeed all carotenoids the ability to isomerize and
thus numerous combinations of cis and trans isomers are
possible. The most thermodynamically stable configuration is the all-trans configuration and it is this isomer of
lycopene that is most commonly found in raw foods.
However, cooking or other types of food processing can
cause isomerization leading to increased levels of
Prostate Cancer and Prostatic Diseases
Lycopene and prostate cancer
NJ Barber and J Barber
8
cis-isomers, particularly 5-cis.6 In biology, the absorption
of light, exposure to energy (eg heat) or chemical reactions
are thought to result in isomeric interconversion.
In truth, little is known regarding the biology of dietary
lycopene in the human gastrointestinal tract. It is
assumed to follow a similar route of absorption as betacarotene. It is likely, therefore, that lycopene is digested
and absorbed in a pattern of events one would expect of a
hydrophobic molecule or lipid, being acted upon by bile
salts and pancreatic lipases and incorporated into micelles
that are absorbed into the mucosal cells by a passive
process. Thereafter, lycopene is transported from the gut
mucosa by chylomicrons and later in the circulation the
bulk of lycopene is found in the hydrophobic core of low
density lipoproteins.7,8 Interestingly, lycopene, like other
carotenoids, is found in tight protein – carotenoid complexes and crystalline aggregates in most foods leading to
some significant barriers to economic absorption. These
tight bonds are dissociated by heating leading to
improved bioavailability and it is well recognized that
heating tomato juice with lipid improves lycopene
absorption.6 Under favourable conditions as much as
30% of lycopene can be absorbed with the rest being
excreted.
Once absorbed it is possible to measure serum concentrations of lycopene and it appears stable in collected
blood samples stored at 7 70 C for many years.9,10
Whilst serum concentrations may vary hugely between
different populations11 – 20 there appears to be much
smaller changes in the serum within an individual
unless significant changes in dietary intake occur; for
both dietary restriction21 and addition22,23 of lycopene
will have gradual effects on serum concentration. To
measure the immediate effect of diet on lycopene absorption it is better to measure chylomicron lycopene content.24 Once in the circulation, lycopene is distributed to
tissues around the body and it is becoming increasingly
clear that this is not a uniform process. Significantly
higher concentrations of lycopene, compared to the
other carotenoids, are found in the liver, the adrenal
glands, the testes and the prostate gland.14,25 – 30 Once
again, however, the interpersonal variation of tissue lycopene content is large (up to 100-fold). The efficiency of the
digestive and absorptive pathway from dietary intake of
lycopene to absorption into the serum and transport to
the tissues has not been widely investigated. Furthermore, there is significant variation in the types of isomers
measured in the plasma as compared to prostate tissue. In
foodstuffs approximately 5 – 10% of total lycopene
appears as cis isomers as compared to about 50% in
plasma and about 80% in prostate tissue.28,31,32 The
relative importance of this is not clear, particularly in
any active biological role lycopene may play within the
prostate. However, given that cis isomers dissolve better
in lipophilic solutions compared to trans isomeric forms,
which tend to aggregate and crystallize, trans-membrane
movement of the cis isomer into cells may be relatively
facilitated. Lycopene does seem to be a major carotenoid
in the prostate, however, the two studies that have
examined this to date appear to differ as to relative
quantities of the carotenoids found.28,33 In the more
recent study,33 lycopene levels in the prostate tissue
ranked third behind beta-carotene and lutein and this
appeared to reflect relative plasma concentrations. This
Prostate Cancer and Prostatic Diseases
would tend to suggest that lycopene is not preferentially
taken up by the prostate and that uptake from the plasma
to prostate tissue is a passive process from the serum
lipoproteins in which carotenoids are transported. Thus
increased levels of lycopene in prostate tissue is expected
when its plasma concentration is high due to a lycopene
rich diet.
Dietary sources of lycopene
Lycopene is found in a relatively narrow range of foods
and its content in these foodstuffs has been measured in a
number of laboratories (Table 1).31,34 – 36
The principal source of dietary lycopene is undoubtedly tomatoes in most people’s diets, however, lycopene
content varies in different varieties of tomatoes and it is
important to realize that tomatoes contain a whole
different variety of carotenoids other than lycopene.
Although sensitive to isomerization, lycopene is relatively stable when cooked.37,38 Indeed, as mentioned
earlier, the bioavailability of lycopene appears to be
enhanced by processing and cooking.6 Ingestion of
tomato paste leads to greater rises in both serum chylomicron trans and cis isomers of lycopene compared to
that of fresh tomatoes when both are given with corn oil
to aid absorption.39
The accurate estimation of lycopene intake is dependent both on the accuracy of food frequency questionnaires and also on the food composition databases
employed. Unfortunately significant quantitative differences in estimated lycopene intake may be observed if
different databases are used in analyzing the results of
the same food intake questionnaire although qualitatively individuals are similarly ranked in terms of high
or low intake of lycopene.24 Thus, self reported food
questionnaires and estimation of lycopene intake calculated from databases thereafter does appear to rank
intake correctly40,41 but lacks quantitative accuracy. It
does seem that such food questionnaires cannot be
used confidently to estimate the lycopene (or indeed
any carotenoid) content of the prostate however.33
Whether this conclusion of Freeman et al. reflects the
small numbers in the study (n ¼ 47) or the methodology employed (particularly of tissue sampling) is open
to question. The authors themselves held the self-report
of dietary intake as the most likely source of any error.
However, accurate data of lycopene content in cooked
vegetables was not incorporated into a comprehensive
database until 199842 and this was not used in this
study, perhaps leading to another source of error. Other
studies have demonstrated good associations between
dietary carotenoid intake and plasma levels43 and,
importantly, plasma levels of all the antioxidants measured did correlate well with prostatic tissue levels in
this study. Further larger studies or well designed
feeding studies or studies requiring more accurate
dietary assessments will be required to demonstrate
the relationship between lycopene intake and prostatic
levels.44 Moreover, the important influence of other
concurrent dietary factors on the efficiency of intestinal
lycopene absorption need to be included in any database.
Lycopene and prostate cancer
NJ Barber and J Barber
Lycopene and the biology of cancer
For some time the role of the oxidative damage to cellular
protein, lipid and most importantly DNA has been proposed as a possible mechanism of the evolution of cancer,
including prostate cancer.45,46 The oxidative weapons are
free radicals, which are molecules with an unpaired
electron on the outer shell. There are intrinsic defense
mechanisms against cellular damage by these free radicals including the enzymes glutathoine peroxidase and
superoxide dismutase. Not surprisingly, interest has
developed in exogenous sources of antioxidants and
these include vitamin E, vitamin A, selenium and carotenoids including lycopene.47 Carotenoids may react with
oxygen free radicals by either transfer of the unpaired
electron leaving the carotenoid in an excited triplet state,
the excess energy being dissipated as heat, or by ‘bleaching’ of the carotenoid. The former leaves the carotenoid
intact and therefore able to be involved in numerous
cycles of free radical scavenging, the latter results in
decomposition of the carotenoid. Fortunately, it is the
former that predominates and the efficiency of this process seems to be related to the number of double bonds
incorporated in the carotenoid structure. Interest has been
heightened in lycopene, in particular, as it has a large
number of double bonds and thus has been found to be
the most potent scavenger of oxygen free radicals of all
the carotenoids.48 Lycopene has been demonstrated to not
only scavenge oxygen free radical species, for example
peroxyl radicals, but also interact with reactive oxygen
species such as hydrogen peroxide and nitrogen dioxide49 – 51 and in this manner protect cells from oxidative
damage. Interestingly lycopene was found to be twice as
efficient as beta-carotene in scavenging for nitrogen dioxide.49,52 Lycopene has also been demonstrated to have
other possible anti cancer activities particularly relating to
modulation of intercellular communication and alterations in intracellular signalling pathways.53 These include
an upregulation in intercellular gap junctions,54 an
increase in cellular differentiation55 and alterations in
phosphorylation of some regulatory proteins.56 Little is
known regarding the role or indeed importance of these
effects in vivo, however, lycopene has been demonstrated
to be significantly more efficient than any carotene in
inhibiting insulin-like growth factor type 1 (IGF1)
induced proliferation of a number of tumour cell lines57
and decrease the occurrence of both spontaneous and
chemically induced mammary tumours in animal
models.58,59 In prostate cancer, in particular, a study has
demonstrated inhibition of cell line proliferation in the
presence of physiological concentrations of lycopene in
combination with alpha-tocopherol.60 Interestingly, a
large study has linked lower levels of IGF1 (high levels
of which are associated with the incidence of prostate
cancer61) with increased tomato intake in the diet.62
Lycopene and prostate cancer
The interest in the possible anti cancer properties of
carotenoids and more recently lycopene itself are based
not only on a sound scientific basis, but also on a wealth
of epidemiological data from around the world. Numerous studies have demonstrated associations of higher
dietary fruit and vegetable intake with lower risks of a
whole range of cancers. The strength of the evidence is
such that the National Research Council of the Academy
of Sciences,63 the National Cancer Institute64 and the
World Cancer Research Fund and the American Institute
for Cancer Research65 have all recommended increasing
dietary intake of citrus fruits, cruciferous vegetables,
green and yellow vegetables and fruit and vegetables
high in vitamins A and C to lower cancer risk. Similar
recommendations have been made by the UK government66 and by the World Health Organization.67 However, it was analysis of data from the HPFU study that
initially proposed the possible importance of relative
intake of lycopene as opposed to other chemicals found
in fruit and vegetables on the risk of prostate cancer.5 Of
nearly 50 000 men, 812 developed prostate cancer. Of the
dietary variables measured (including alpha- and betacarotene) only lycopene was associated with a decreased
risk (21%) of prostate cancer (age and energy adjusted
RR ¼ 0.79; 95% confidence interval ¼ 0.64 – 0.99 for high
vs low quintile intake). In this study high intake of
tomatoes and tomato products (accounting for 82% of
lycopene intake) reduced the total risk of prostate cancer
by 35% and of high grade cancer by 53%. Those in the
higher quintile were said to consume more than 10
servings of lycopene per week as opposed to less than
one in the lower quintile. Perhaps related to changes in
bioavailability as outlined above, it was also found that
the consumption of tomato sauce as opposed to tomato
juice has the strongest inverse association (RR ¼ 0.66, 95%
confidence interval ¼ 0.49 – 0.90; P for trend ¼ 0.001). It is
important to note that this study is one of some 17
studies5,68 – 83 that has examined dietary carotenoid
intake and the risk of prostate cancer and whilst two
have found protective effects for beta-carotene only the
study by Giovannuci et al 5 has shown an effect related to
lycopene. Moreover, of the seven studies that specifically
examined whether dietary tomato products in particular
reduce the risk of prostate cancer, only three found this to
be the case.5,84,85 One further is inconclusive statistically
but tends to support that hypothesis86 and three found no
association at all.73,87,88 However, one of the latter three
negative studies73 did describe a strong dietary association of decreased risk of prostate cancer with the
consumption of tinned baked beans (RR ¼ 0.52; 95%
confidence interval ¼ 0.31 – 0.88) and the authors did
suggest that tinned baked beans do provide a large
amount of highly bioavailable lycopene.
A number of studies have examined a similar association with plasma lycopene levels rather than dietary
intake. Three have shown a negative association with
the risk of prostate cancer89,90,91 and one showed no
link.92 In one study,89 a statistically non significant 6.2%
lower median lycopene level was demonstrated in those
who developed prostate cancer compared to age and race
matched controls (RR ¼ 0.50 95%CI ¼ 0.20 – 1.29) between
high and low quartiles of plasma lycopene and another
(based on 581 subjects)90 a statistically significant RR of
0.56% (95%CI ¼ 0.34 – 0.91) was demonstrated when comparing high quintile with low quintile of plasma lycopene.
In comparing both dietary studies and plasma studies
one must remember the huge interpersonal and indeed
9
Prostate Cancer and Prostatic Diseases
Lycopene and prostate cancer
NJ Barber and J Barber
10
intercultural differences in lycopene levels, as outlined
above, and recognize that some of the unsupportive
studies relate to populations with low base-line dietary
intake and plasma levels.88,92
Conclusions
In order to clarify the muddied waters as to whether any
proposed association truly exists between ingestion of
lycopene and reduced frequency of prostate cancer,
further studies should aim to separate the effects of
vegetables in general from that of tomatoes. It may be
that lycopene merely represents a good marker of vegetable and fruit intake and that people who eat large
quantities of fruit and vegetables tend to be those who
are more health conscious and one could argue also avoid
high cancer risk behavior anyway. On the other hand,
those same health conscious people are more likely to
seek ‘screening’ for prostate cancer and thus be diagnosed
with the disease. It is also important to realize that
lycopene rich foodstuffs are not necessarily linked to
vegetable intake, such as ketchup, pizzas and tomato
sauces and as such may be fairly viewed as a separate
dietary factor from vegetable intake. Further studies
should employ dietary questionnaires and nutrient databases that are specifically sensitive to lycopene.44
Of all the carotenoids, beta-carotene has been most
investigated, particularly in relation to decreasing risk of
smoking related cancers. It is important to note, however,
that two trials of supplemental beta-carotene actually
seemed to lead to an increased risk of lung cancer in
male smokers of 28%93 and 18%94 in the treated vs
untreated arms. The results of this study serve to warn
that fruits and vegetables contain a whole range of
biologically active substances and to choose one for dietary supplementation must be a carefully made decision
based on good scientific data. One must therefore view
with caution the potentially exciting results from the
Karmanos Cancer Institute, Detroit.95 A prospective,
single blind, placebo controlled, randomized study was
performed where 15 of 26 men scheduled for radical
prostatectomy for organ confined malignacy were given
lycopene supplements, 15 mg twice a day (Lyc – O –
Mato2, LycoRed, Beer-Sheva, Israel) for 3 weeks pre
operatively. Serial measurements confirmed a 22%
increase in plasma and tissue lycopene levels and a
statistically significant fall in prostate specific antigen
(PSA) over the 3 weeks in those taking lycopene. Those
in the supplement arm were also found to have smaller
volume tumours and surgical margins were less likely to
be positive. Furthermore, analysis of the excised tissue
showed that biomarkers of cellular proliferation
decreased, whereas those of cellular differentiation,
including connexin 43, and apoptosis increased in the
intervention arm. Clearly this trial is too small in size to
draw any real conclusions, however, it certainly adds fuel
to the fire of debate. However, given the paucity of
knowledge of the phamacokinetic properties of lycopene,
of the potential risks of excess dietary intake and any hard
scientific evidence as to its benefits, it is premature to
recommend pharmacological supplementation of lycopene. Any dietary recommendations, therefore, should
Prostate Cancer and Prostatic Diseases
be based on those from the organizations listed above that
emphasize the general benefits of diets high in a whole
variety of vegetables and fruits, including tomatoes and
tomato-based products.
References
1 Willet WC. Specific fatty acids and risks of breast and prostate
cancer: dietary intake. Am J Clin Nutr 1997; 66: 1557 – 1563
2 Giovannucci E. Epidemiologic characteristics of prostate cancer.
Cancer 1995; 75: 1766 – 1777.
3 Haenszel W, Kurihara M. Studies of Japanese migrants. Mortality
from cancer and other diseases among Japanese in the United
States. J Natl Cancer Inst 1968; 40: 43 – 68.
4 Staszewski W, Haenszel W. Cancer mortality among Polish-born
in the United States. J Natl Cancer Inst 1965; 35: 291 – 297.
5 Giovannucci E et al. Intake of carotenoids and retinol in relation
to risk of prostate cancer. J Natl Cancer Inst 1995; 87: 1767 – 1776.
6 Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is
greater from heat processed than unprocessed tomato juice in
humans. J Nutr 1992; 122: 265 – 277.
7 Parker RS. Absorption, metabolism and transport of carotenoids.
FASEB J 1996; 10: 542 – 551.
8 Krinsky NI, Cornwell GD, Oncley JL. The transport of vitamin A
and carotenoids in human plasma. Arch Biochem Biophys 1958; 73:
233 – 246
9 Gross MD, Prouty CB, Jacobs DR. Stability of carotenoids and
alpha-tocopherol during blood collection and processing procedures. Clin Chem 1995; 41: 943 – 944.
10 Comstock GW et al. Stability of ascorbic acid, carotenoids, retinol
and tocopherols in plasma stored at 7 70 C for 4 y. Cancer
Epidemiol Biomarkers Prev 1995; 4: 505 – 507.
11 Gerster H. The potential role of lycopene for human health. J Am
Coll Nutr 1997; 16: 109 – 126.
12 Campbell DR et al. Plasma carotenoids as biomarkers of fruit and
vegetable intake. Cancer Epidemiol Biomarkers Prev 1994; 3: 493 –
500.
13 Brady WE, Mares-Perlman JA, Bowen P, Stacewicz-Sapuntzakis
M. Human serum carotenoid concentrations are related to physiologic and lifestyle factors. J Nutr 1996; 126: 129 – 137.
14 Stahl W, Shwartz W, Sundquist AR, Sties H. Cis – Trans isomers of
lycopene and beta carotene in human serum and tissues. Arch
Biochem Biophys 1992; 294: 173 – 177.
15 Carughi A, Hooper FG. Plasma carotenoid concentrations before
and after supplementation with a carotenoid mixture. Am J Clin
Nutr 1994; 59: 896 – 899.
16 Micozzi MS et al. Plasma carotenoid response to chronic intake of
selected foods and beta-carotene supplements in men. Am J Clin
Nutr 1992; 55: 1120 – 1125.
17 Ross MA et al. Plasma concentrations of carotenoids and antioxidant vitamins in Scottish males: influences of smoking. Eur J
Clin Nutr 1995; 49: 861 – 865.
18 Peng YM et al. Concentrations and plasma-tissue-diet relationships of carotenoids, retinoids and tocopherols in humans. Nutr
Cancer 1995; 23: 233 – 246.
19 Pamuk ER et al. Effect of smoking on serum nutrient concentrations in African-American women. Am J Clin Nutr 1994; 59: 581 –
585.
20 Olmedilla B, Granado F, Blanco I, Rojas – Hidalgo E. Seasonal and
sex-related variations in six serum carotenoids, retinol and alpha
tocopherol. Am J Clin Nutr 1994; 60: 106 – 110.
21 Rock CL, Swendseid ME, Jacob RA, McKee RW. Plasma carotenoid levels in human subjects fed a low carotenoid diet. J Nutr
1992; 122: 96 – 100.
22 Carughi A, Hooper FG. Plasma carotenoid concentrations before
and after supplementation with a carotenoid mixture. Am J Clin
Nutr 1994; 59: 896 – 899.
23 Micozzi MS et al. Plasma carotenoid response to chronic intake of
selected foods and beta-carotene supplements in men. Am J Nutr
1992; 55: 1120 – 1125.
Lycopene and prostate cancer
NJ Barber and J Barber
24 Clinton SK. Lycopene: chemistry, biology and implications for
human health and disease. Nutrition Reviews 1998; 56: 35 – 51.
25 Kaplan LA, Lau JM, Stein EA. Carotenoid composition, concentrations and relationships in various human organs. Clin Physiol
Biochem 1990; 8: 1 – 10.
26 Schmitz HH, Poor CL, Wellman RB, Erdman JW Jr. Concentrations of selected carotenoids and vitamin A in human liver,
kidney and lung tissue. J Nutr 1991; 121: 1613 – 1621.
27 Nierenberg DW et al. Effects of 4-year oral supplementation with
beta-carotene on serum concentrations of retinol, tocopherol and
five carotenoids. Am J Clin Nutr 1997; 66: 315 – 319.
28 Clinton SK et al. Cis – trans lycopene isomers, carotenoids and
retinol in the human prostate. Cancer Epidemiol Biomarkers Prev
1996; 5: 823 – 833.
29 Sanderson MJ, White KL, Drake IM, Schorah CJ. Vitamin E and
carotenoids in gastric biopsies: the relation to plasma concentrations in patients with and without Helicobacter pylori gastritis. Am
J Clin Nutr 1997; 65: 101 – 106.
30 Parker RS. Carotenoid and tocopherol composition in human
adipose tissue. Am J Clin Nutr 1988; 47: 33 – 36.
31 Nguyen ML, Shwartz SJ. Carotenoid geometrical isomers in
fresh and thermally processed fruits and vegetables. Proceedings
of the 2nd Karlsruhe Nutrition Symposium, Karlsruhe, Germany
1997.
32 Yeum KJ et al. Human plasma carotenoid response to the ingestion of controlled diets high in fruit and vegetables. Am J Clin
Nutr 1996; 64: 594 – 602.
33 Freeman VL et al. Prostatic levels of tocopherols, carotenoids and
retinol in relation to plasma levels and self-reported usual dietary
intake. Am J Epidemiology 2000; 151: 109 – 118.
34 Scott KJ, Hart DJ. Development and evaluation of an
HPLC method for the analysis of carotenoids in foods, and the
measurement of the carotenoid content of vegetables and
fruits commonly consumed in the UK. Food Chem 1995; 54:
101 – 111.
35 Mangels AR et al. Carotenoid content of fruits and vegetables:
an evaluation of analytical data. J Am Diet Assoc 1993: 93: 284 –
296.
36 Ong SSH, Tee ES. Natural sources of carotenoids from plants and
oils. Methods Enzymol 1992; 213: 142 – 167.
37 Erdman JR Jr, Bierer TL, Gugger ET. Absorption and transport of
carotenoids. In: Canfield LM, Krinsky NI, Olson JA (eds). Carotenoids in Human Health, Vol 691. New York Acadamy of
Sciences: New York, 1993, pp 76 – 85.
38 Zhou JR, Gugger ET, Erdman JR Jr. The crystalline form of
carotenes and the food matrix in carrot root decrease the relative
bioavailability of beta and alpha carotene in the ferret model. J
Am Coll Nutr 1996; 15: 84 – 91.
39 Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from
tomato paste than from fresh tomatoes. Am J Clin Nutr 1997; 66:
116 – 122.
40 Bazzarre T. Comparative evaluation of methods of collecting food
intake data for epidemiological studies. Nutr Cancer 1983; 5: 201 –
214.
41 Siggelbout AM et al. Development and relative validity of a food
questionnaire for the estimation of intake of retinol and betacarotene. Nutr Cancer 1989; 12: 289 – 299.
42 Nutrient Coordinating Centre. Nutrient data system, release 2.9,
MN: University of Minnesota, 1998.
43 Tucker K et al. Carotenoid intakes, assessed by dietary questionnaire, are associated with plasma carotenoid concentrations in an
elderly population. J Nutr 1998; 129: 438 – 445.
44 Kristal AR, Cohen H. Invited commentary: tomatoes, lycopene
and prostate cancer. How strong is the evidence? Am J Epidemiol
2000; 151: 124 – 127.
45 Ripple MO, Henry WF, Rago RP, Wilding G. Pro-oxidant-antioxidant shift induced by androgen treatment of human prostate
carcinoma cells. J Natl Cancer Inst 1997; 89: 40 – 48.
46 Malins DC, Polissar NL, Gunselman SJ. Models of DNA structure
achieve almost perfect discrimination between normal prostate,
benign prostatic hyperplasia and adenocarcinoma and have a
high potential for predicting BPH and prostate cancer. Proc Natl
Acad Sci USA 1997; 94: 259 – 264.
47 Mayne ST. Beta-carotene, carotenoids and cancer prevention. In:
DeVita VT, Hellman S, Rosenberg SA (eds). Cancer Principles and
Practice of Oncology Vol 12. Lippincott-Raven: New Jersey, USA,
1998, pp 2 – 15.
48 Miller NJ et al. Antioxidant activities of carotenes and xanthophylls. FEBS letters 1996; 384: 240 – 246.
49 Bohm F, Tinkler JH, Truscott TG. Carotenoids protect against cell
membrane damage by the nitrogen dioxide radical. Nature Med
1995; 1: 98 – 99.
50 Lu Y et al. A new carotenoid, hydrogen peroxide oxidation
products from lycopene. Biosci Biotech Biochem 1995; 59: 2153 –
2155.
51 Woodall AA et al. Oxidation of carotenoids by free radicals:
relationship between structure and reactivity. Biochim Biophys
Acta (Netherlands) 1997; 1336: 33 – 42.
52 Tinkler JH, Boehm F, Schalch W, Truscott TG. Dietary carotenoids
protect human cells from damage. J Photochem Photobiol 1994; 26:
283 – 285.
53 Stahl W, Sies H. Lycopene: a biologically important carotenoid for
humans? Arch Biochem Biophys 1996; 336: 1 – 9.
54 Zhang LX, Cooney RV, Bertram JS. Carotenoids upregulate connexin 43 gene expression independent of their provitamin A or
antioxidant properties. Cancer Res 1992; 52: 5707 – 5712.
55 Bankson DD, Countryman CJ, Collins SJ. Potentiation of the
retinoic acid-induced differentiation of HL-60 cells by lycopene.
Am J Clin Nutr 1991; 53(Suppl): 13.
56 Matsushima-Nishiwaki R et al. Suppression by carotenoids of
microcystin-induced morphological changes in mouse hepatocytes. Lipids 1995; 30: 1029 – 1034.
57 Levy J et al. Lycopene is a more potent inhibitor of human cancer
cell proliferation than either alpha-carotene or beta-carotene. Nutr
Cancer 1995; 24: 257 – 266.
58 Nagasawa H, Mitamura T, Sakamoto S, Yamamoto K. Effects of
lycopene on spontaneous mammary tumour development in
SHN virgin mice. Anticancer Res 1997; 15: 118 – 123.
59 Sharoni Y, Giron E, Rise M, Levy J. Effects of lycopene-enriched
oleoresin on 7,12-dimethyl-benz[a]anthracene-induced rat mammary tumours. Cancer Detect Prev 1997; 21: 118 – 123.
60 Pastori M, Pfander H, Boscoboinik D, Azzi A. Lycopene in
association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate cancer cells. Biochem Biophys
Res Commun 1998; 250: 582 – 585.
61 Chan JM et al. Plasma insulin like growth factor 1 and prostate
cancer risk; a prospective study. Science 1998; 279: 563 – 566.
62 Mucci LA et al. Are dietary influences on the risk of prostate
cancer mediated through the insulin-like growth factor system?
BJU International 2001; 87: 814 – 820.
63 US National Research Council Committee on diet and health:
implications for reducing chronic disease risk. National Academy
Press: Washington (DC), 1989.
64 National Cancer Institute. Diet, nutrition and cancer prevention:
a guide to food choices. US Govt Print Off: Washington (DC),
1987.
65 World Cancer Research Fund American Institute for Cancer
Research. Food, nutrition and the prevention of cancer: a global
prospective. American Institute for Cancer Research: Washington
(DC), 1997.
66 Committee on Medical Aspects of Food and Nutrition Policy
(COMA) 1998 Annual Report, UK. Published in 1999 by the
Department of Health (UK).
67 Diet, nutrition and the prevention of chronic diseases. Technical
Report Series 797, WHO: Geneva, 1990.
68 Ohno Y et al. Dietary beta-carotene and cancer of the prostate: a
case-control study in Kyoto, Japan. Cancer Res 1988; 48: 1331 –
1336.
69 Hsing AW et al. Diet, tobacco use and fatal prostate cancer: results
from the Lutheran Brotherhood Cohort Study. Cancer Res 1990;
50: 6836 – 6840.
70 La Vecchia C et al. Dairy products and the risk of prostate cancer.
Oncology 1991; 48: 406 – 410.
71 Le Merchand L et al. Vegetable and fruit consumption in relation
to prostate cancer risk in Hawaii: a re-evaluation of the effect of
dietary beta-carotene. Am J Epidemiol 1991; 133: 215 – 219.
11
Prostate Cancer and Prostatic Diseases
Lycopene and prostate cancer
NJ Barber and J Barber
12
72 Ross RK et al. Case – control study of prostate cancer in blacks
and whites in Southern California. J Natl Cancer Inst 1987; 78:
869 – 874.
73 Key T et al. A case – control study of diet and prostate cancer. Br J
Cancer 1997; 76: 678 – 687.
74 Kolonel LN et al. Relationship of dietary vitamin A and ascorbic
acid intake to the risk of cancers of the lung, bladder and prostate
in Hawaii. Natl Cancer Inst Monogr 1985; 69: 127 – 142.
75 Kolonel LN, Hankin JH, Yoshizawa CN. Vitamin A and prostate
cancer in elderly men: enhancement of risk. Cancer Res 1987; 47:
2982 – 2985.
76 Oishi K et al. A case control study of prostate cancer with
reference to dietary habits. Prostate 1988; 12: 179 – 190.
77 Mettlin C et al. Beta-carotene and animal fats and their relationship to prostate cancer risk: a case-control study. Cancer 1989; 64:
605 – 612.
78 West DW et al. Adult dietary intake and prostate cancer risk in
Utah: a case – control study with special emphasis on aggressive
tumours. Cancer Causes Control 1991; 2: 85 – 94.
79 Rohan TE et al. Dietary fibre, vitamins A, C and E and risk of
breast cancer: a cohort study. Cancer Causes Control 1993; 4: 29 –
37.
80 Andersson S et al. Energy, nutrient intake and prostate cancer
risk: a population based case control study in Sweden. Int J
Cancer 1996; 68: 716 – 722.
81 Daviglus M et al. Dietary beta-carotene, vitamin C and the risk of
prostate cancer: results from Western Electric Study. Epidemiology
1996; 7: 472 – 477.
82 Ghadirian P et al. Nutritional factors and prostate cancer: a casecontrol study of French Canadians in Montreal, Canada. Cancer
Causes Control 1996; 7: 428 – 436.
83 Meyer F et al. Dietary energy and nutrients in relation to
preclinical prostate cancer. Nutr Cancer 1997; 29: 120 – 126.
84 Tzonou A et al. Diet and cancer of the prostate: a case-control
study in Greece. Int J Cancer 1999; 80: 149 – 155.
Prostate Cancer and Prostatic Diseases
85 Mills PK et al. Cohort study of diet, lifestyle and prostate cancer
in Adventist men. Cancer 1989; 64: 598 – 604.
86 Norrish AE, Jackson RT, Sharpe SJ, Murray Skeaff C. Prostate
cancer and dietary carotenoids. Am J Epidemiol 2000; 151: 119 –
123.
87 Schuman L, Mandel J, Radke A. Some selected features of the
epidemiology of prostate cancer: Minneapolis-St Paul, Minnesota
case – control study, 1976 – 1979. In: Magnus K, (ed). Trends in
Cancer Incidence: Causes and Implications. Hemisphere Publishing
Corporation: Washington, DC, 1982, pp 345 – 354.
88 Schuurman AG et al. Vegetable and fruit consumption and
prostate cancer risk: a cohort study in the Netherlands. Cancer
Epidemiol Biomarkers Prev 1998; 7: 673 – 680.
89 Hsing AW et al. Serologic precursors of cancer. Retinol, carotenoids and tocopherol and risk of prostate cancer. J Natl Cancer
Inst 1990; 82: 941 – 946.
90 Gann P et al. Lower prostate cancer risk in men with elevated
plasma lycopene: results of a prospective analysis. Cancer Res
1999; 59: 1225 – 1230.
91 Rao AV, Fleschner G, Agarwal A. Serum and tissue lycopene and
biomarkers of oxidation in prostate cancer patients: a case –
control study. Nutr and Cancer 1999; 33: 159 – 164.
92 Nomura AM et al. Serum micronutrients and prostate cancer in
Japanese Americans in Hawaii. Cancer Epidemiol Biomarkers Prev
1997; 6: 487 – 491.
93 Omenn GS et al. Effects of a combination of beta-carotene and
vitamin A on lung cancer and cardiovascular disease. New Engl J
Med 1996; 334: 1150 – 1155.
94 The Alpha Tocopherol, Beta-Carotene Cancer Prevention Study
Group. The effect of vitamin E and beta-carotene on the incidence
of lung cancer and other cancers in male smokers. New Engl J Med
1994; 330: 1029 – 1035.
95 Kucuk O et al. Phase II randomized clinical trial of lycopene
supplementation before radical prostatectomy. Cancer Epidemiology, Biomarkers and Prevention. 2001; 10: 861 – 868.