Detoxifying Cancer Causing Agents
DetoxifyingetCancer
10.1177/1534735403253305
Hanausek al Causing Agents
Detoxifying Cancer Causing
Agents to Prevent Cancer
Margaret Hanausek, PhD, Zbigniew Walaszek, PhD, and Thomas J. Slaga, PhD
Different vitamins and other micronutrients in vegetables,
fruits, and other natural plant products may prevent cancer
development (carcinogenesis) by interfering with detrimen-
tal actions of mutagens, carcinogens, and tumor promoters.
The goal of current studies in cancer prevention is to deter-
mine the mechanisms of synergistic action of the natural
source compounds known to inhibit one or more stages of
carcinogenesis, that is, initiation and promotion/progres-
sion. Many natural cancer preventive agents are effective in-
hibitors of tumor initiation, promotion, and/or progression.
The mechanism of action is related to their abilities to pre-
vent critical carcinogen metabolism and to increase detoxifi-
cation of carcinogens and tumor promoters. The authors
review here the potential role of the detoxification system
and, in particular, the roles of D-glucaric acid and the enzyme
β-glucuronidase in early detection and prevention of cancer.
There is now growing evidence for the possible control of
different stages of the cancer induction by inhibiting β-
glucuronidase with D-glucaric acid derivatives, especially
with its salts (D-glucarates). D-Glucaric acid has been found
in many vegetables and fruits. Therefore, the consumption
of fruits and vegetables naturally rich in D-glucaric acid or
self-medication with D-glucaric acid derivatives such as cal-
cium D-glucarate offers a promising cancer prevention ap-
proach.
Keywords: Carcinogens; detoxification; natural products; cancer
prevention
Detoxification System and
Chemoprevention of Cancer
Inhibition of the induction of cancer (carcinogenesis)
and the prevention of cancer with chemical com-
pounds is usually referred to as chemoprevention.
Chemopreventive agents, which prevent cancer-
causing agents (carcinogens) from reaching or react-
ing with critical targets (cancer initiation) are called
blocking agents, whereas those preventing the evolu-
tion of the neoplastic process in cells (cancer promo-
1
tion and progression) are called suppressing agents.
Currently, a number of blocking and suppressing
agents are being tested using either pharmacological
DOI: 10.1177/1534735403253305
INTEGRATIVE CANCER THERAPIES 2(2); 2003 pp. 139-144
or, less often, nutritional regimens. Chemopreventive
blocking agents can prevent the occurrence of cancer
by increasing the detoxification of chemical carcino-
gens, tumor promoters, and tumor progressors. The
2
pathways of detoxification have been divided into 2
major categories: phase I reactions (oxidations, reduc-
tions, and hydrolyses) and phase II reactions (conju-
gations). Both phase I and II reactions are to make the
toxin molecule more polar or water soluble and there-
fore readily excreted. There has been a growing inter-
est in the inhibitors that induce an increase in activity
of phase II detoxifying enzymes, with a special empha-
sis on glutathione S-transferases.2 Glutathione S-trans-
ferases conjugate ultimate carcinogens, that is, very
reactive electrophilic metabolites of carcinogenic
compounds, with glutathione.
There is also strong evidence for the detoxification
of chemical carcinogens or their metabolites and
tumor promoters/progressors by UDP-glucuronosyl-
transferases,2 which conjugate nucleophilic com-
pounds produced by our bodies (endogenous) as well
as foreign chemicals (exogenous), with D-glucuronic
acid. Conjugation with D-glucuronic acid, that is,
glucuronidation, appears to be the principal conjuga-
tion pathway in the tissues of all vertebrate species
examined to date.3 The conjugates are excreted in the
bile and urine or transported from one tissue (usually
liver) to other tissues. UDP-glucuronosyltransferases
are found in the endoplasmic reticulum and nuclear
membranes and are markedly inducible by xenobiotic
inducers (foreign compounds).4 High specific activity
of nuclear UDP-glucuronosyltransferase in the
nuclear membrane in proximity to genetic material
suggests a very important role in the deactivation of
both foreign and endogenous compounds such as ste-
roid hormones. Thus, this enzyme could also serve as
an important barrier for the nuclear genetic appara-
tus against mutagenic and carcinogenic or otherwise
MH, ZW, and TJS are at the AMC Cancer Research Center, Den-
ver, Colorado
Correspondence: Margaret Hanausek, PhD, AMC Cancer Re-
search Center, 1600 Pierce Street, Denver, CO 80214. E-mail:
hanausekm@amc.org.
139
 Hanausek et al

5
toxic chemical compounds. Carcinogens identified D-Glucaro-1,4-Lactone

to date, which after metabolic activation are subject to CO

glucuronidation, include polycyclic aromatic hydro- HC OH

carbons, some nitrosoamines, aromatic amines, and H OCH

fungal toxins. Certain tumor promoters including ste- HC O

roid hormones also undergo glucuronidation.3 CH OH CO HC OH COOH

The importance of conjugating enzymes such as HC OH HCOH C OOH H COH

OCH OCH HOCH

UDP-glucuronosyltransferase, which uses nucleo-
HC O HCO HCOH
philic substrates instead of reactive electrophiles, has HC OH HCOH COOH H COH
only recently been recognized.2 It has become appar- CO CO HC OH COOH

ent that nucleophilic metabolites are often intermedi- OCH

D-Glucaric Acid
ates in formation of ultimate carcinogens. Further- D-Glucurono-6,3-Lactone HC OH

more, it is clear that glucuronides may be highly stable HC OH

forms of these intermediates, which are subject to fur- CO

ther activation after hydrolysis by the enzyme β-

glucuronidase at sites distant from their site of forma-
tion.6 In fact, the elimination and or deactivation of
potentially damaging chemicals that undergo
glucuronidation is limited not only by the rate of con-
jugation with D-glucuronic acid but also by the rate of
de-glucuronidation by this ubiquitous enzyme.3
Novel Biomarkers of Detoxification System:
D-Glucaric Acid and ␤-Glucuronidase
The availability of effective chemoprevention agents is
only one component of a full chemoprevention pro-
gram. Another important component is the availabil-
ity of a marker or markers that can help evaluate the
effects of chemopreventive agents early during the
prevention trials and evaluate individuals as to the
magnitude of general or site-specific risk to cancer. In
fact, the development of intermediate biomarkers of
cancer risk and the evaluation of efficacy of individual
biological or molecular markers as intermediate end
points in prevention trials have been considered as im-
portant avenues in cancer research.
Recently, the potential role of the detoxification
system and the roles of D- glucaric acid and β-
glucuronidase in early detection and prevention of
cancer have been investigated. D-Glucaric acid is a nat-
ural, apparently nontoxic compound produced by
some plants, especially in fruits and vegetables, and in
small amounts by mammals, including humans.7 D-
Glucaric acid is an end product of the D-glucuronic
acid pathway in mammals.7 Oxidation of D-glucuronic
acid or its lactone leads to oxidation products that
hydrolyze spontaneously in aqueous solution to give
the potent β-glucuronidase inhibitor, D-glucaro-1,4-
lactone, noninhibitory D-glucaro-6,3-lactone, and D-
glucaric acid (see Figure 1), all of which are excreted
in urine.7 D-Glucaric acid was identified as a normal
constituent of urine7 and serum.8 In fact, D-glucaric
acid is a major serum organic acid.8 However, signifi-
cant differences in serum levels and urinary excretion
D-Glucaro-6,3-Lactone
Figure 1 In vivo formation of the -glucuronidase inhibitor D-
glucaro-1,4-lactone by oxidation of D-glucuronic acid
lactone.
8,9
of D-glucaric acid have been reported for apparently
healthy people. Since urinary excretion of D-glucaric
acid increases following exposure to xenobiotics, it
was suggested for use as an indirect indicator of
hepatic microsomal enzyme induction by xenobiotic
10
agents. D-Glucaric acid urinary excretion in cancer
patients and tumor-bearing rats was found11 to be sig-
nificantly lower than in healthy controls. In mice with
experimental tumors and in cancer patients, unin-
volved liver had a lowered D-glucaric acid level.7 Can-
cer tissue itself lacked the D-glucaric acid synthesizing
system.7
The physiological function of D-glucaric acid is
unclear. Formation of D-glucaro-1,4-lactone, an inhibi-
tor of β-glucuronidase, from one of the products of its
hydrolytic action (ie, D-glucuronic acid), could be
regarded as a negative feedback mechanism. The
accumulation in the body of free carcinogens, tumor
promoters, and other toxins, normally excreted as
glucuronides in the bile or urine, may be aggravated
not only by the elevated β-glucuronidase activity but
also by the depressed synthesis of the β-glucuronidase
inhibitor D-glucaro-1,4-lactone (Figure 2). D-Glucaro-
1,4-lactone does not directly affect the UDP-glu-
curonosyltransferase activity.3 However, by inhibiting
β-glucuronidase, it does enhance net glucuron-
idation. Therefore, it has a potential for chemo-
prevention of cancer. 12,13 There is now growing
evidence12-14 from short- and long-term models for the
possible control of different stages of the carcinogenic
process by D-glucaro-1,4-lactone, and specifically by its
precursors such as D-glucaric acid salts (D-glucarates).
Recently, D-glucaric acid and has been found in some
15
vegetables and fruits. Thus, the consumption of

140 INTEGRATIVE CANCER THERAPIES 2(2); 2003


Figure 2 The effect of calcium D-glucarate and D-glucaro-1,4-
lactone on detoxification of compounds that undergo
glucuronidation.
fruits and vegetables naturally rich in D-glucaric acid,
or self-medication with D-glucaric acid derivatives such
as calcium D-glucarate or potassium hydrogen D-
glucarate, offers a promising chemopreventive
approach.
The ability to inhibit chemical carcinogenesis by
inhibiting β-glucuronidase activity has some interest-
ing implications. For example, certain subpopulations
may be more susceptible to chemical carcinogens
because of high β-glucuronidase activity. There is
good evidence for human subpopulations with high
and low β-glucuronidase levels. Also, β-glucuronidase
levels are higher in 25- to 60-year-old males, in preg-
nant women, and in workers exposed to certain envi-
ronmental carcinogens. In animal models, β-
glucuronidase activity increases significantly after
both tobacco smoke exposure and oral tobacco
administration. Although most of this evidence
(reviewed earlier12,13) relative to subpopulations,
which may be particularly susceptible to carcinogens,
is circumstantial, it does suggest that the association
between β-glucuronidase activity and chemical
carcinogenesis in animal models, or cancer incidence
in human subpopulations, warrants further study.
Because urinary excretion of D- glucaric acid
increases following exposure to xenobiotics, includ-
ing different toxins and environmental carcinogens,
urinary excretion of D-glucaric acid is considered use-
ful as a nonspecific parameter for exposure to envi-
ronmental factors.16 In fact, very often, the results of
the D-glucaric acid tests correlate well with the results
of bacterial urinary assays for mutagenic activity, that
is, the Ames test.16 In relatively small population studies,
smoking has been found to have no effect or to cause a
significant increase.9 However, the tobacco use extent,
that is, light versus heavy tobacco use, has not been
clearly stated in the above studies. Disease states
INTEGRATIVE CANCER THERAPIES 2(2); 2003
Detoxifying Cancer Causing Agents
known to be accompanied by increased excretion of D-
glucaric acid include alcoholism, early stage of renal
16
disease in children, and liver diseases. Decreased val-
ues of D-glucaric acid excretion have been found to
occur in patients with congestive heart failure, starva-
16
tion, severe burns, and favism. However, intraindividual
variations in urinary excretion of D-glucaric acid have
been reported.16 Since the total daily urine collection
is often impractical and unreliable, it was proposed to
determine the blood serum levels of D-glucaric acid in
cancer patients. It was found17 that normal levels of D-
glucaric acid in the blood serum of healthy people are
1.42 ± 0.5 µM in women and 1.50 ± 0.29 µM in men. In
cancer patients, the blood serum concentration of D-
glucaric acid drops significantly, that is, to levels usu-
ally lower then 1 µM.17
Recently, a Phase I clinical trial was undertaken to
begin to explore the potential role of D-glucaric acid
in the prevention of cancer in humans.18 Current
smokers and nonsmokers, both men and women,
were assigned to escalating doses of calcium D-
glucarate (from 1.5 to 9.0 gm/day) given over a 6-week
period. Blood levels of D- glucaric acid and β-
glucuronidase were determined at baseline and every
2 weeks. In addition, lymphocytes and sputum specimens
were collected for K-ras oncogene determination. A
consistent suppression of β-glucuronidase levels was
achieved by increasing doses of calcium D-glucarate,
which, in turn, correlated well with increasing D-
glucaric acid blood levels. DNA was isolated from the
lymphocyte fraction of the blood and sputum
obtained from male and female smokers and non-
smokers (baseline). Mutated K-ras, an oncogene
linked to lung cancer, was found in the DNA isolated
from baseline blood lymphocytes and from sputum of
some male smokers. No K-ras mutations were found in
nonsmokers. The baseline D-glucaric acid level in the
blood of smokers with mutated K-ras was significantly
lower (ie, by circa 34%, P < .05) than in other smokers
or nonsmokers. No unusual toxicity was encountered
in this Phase I study, and calcium D-glucarate was well
tolerated, even at the highest dose levels.18 Thus, cal-
cium D-glucarate supplementation has potential for
reducing the risk of lung cancer development in
tobacco smokers. The results of extensive animal
studies12,13 also suggest that calcium D-glucarate may
reduce the risk of lung as well as breast, prostate, liver,
skin, and colon cancer in humans.
Importance of Natural
Inhibitors of Carcinogenesis
Scores of epidemiologic studies have noted a lower
risk of cancer among persons whose diet include a rel-
atively large amount of vegetables, fruits, and other
141
 Hanausek et al
19,20
plant products. A popular explanation, both within
the scientific community and among members of the
public, is that different vitamins and other micronutri-
ents in vegetables, fruits, and other natural plant prod-
ucts prevent carcinogenesis by interfering with
detrimental actions of mutagens, carcinogens, and tu-
mor promoters. These natural inhibitors of carcino-
genesis are apparently nontoxic or markedly less toxic
than synthetic chemopreventive agents. Although it is
generally accepted that a diet of large amounts of veg-
etables, fruits, and other plant products lowers cancer
incidence, there is still a need to identify the most ef-
fective constituents of the diet as well as to elucidate
their mechanisms of action.
There has been significant progress in the under-
standing of the multistage nature of carcinogenesis21-23
2,24,25
and the mechanisms of cancer prevention. The
mouse skin model, which represents one of the best
understood experimental models of multistage
carcinogenesis, has permitted the resolution of three
distinct stages: initiation, promotion, and progres-
sion.21,22 It is now apparent that the cellular evolution
to malignancy involves the sequential alteration of
proto-oncogenes26 and/or tumor suppressor genes,27
whose gene products participated in critical pathways
for the transduction of signals and/or regulation of
gene expression.
One of the goals of current studies in cancer pre-
vention is to determine the mechanisms of synergistic
action of the natural source compounds, known to
inhibit one or more stages of carcinogenesis, that is,
initiation and promotion/progression.2,24 The basic
theory underlying these studies is that concurrent
treatment with various natural source inhibitors of dif-
ferent stages of carcinogenesis results in synergistic
effects, leading to more efficient prevention of cancer.
The mechanisms that focus on initiation events
include (a) inhibition or alteration of phase I enzymes
responsible for the formation of reactive carcinogenic
metabolites ultimately leading to their reduced forma-
tion; (b) inhibition or induction of oxidative enzyme
pathways that produce products of lower carcinogenic
potential; (c) induction of detoxification enzymes
(phase II enzymes) and pathways (nonoxidative) for
both proximate and ultimate carcinogen; (d) scaveng-
ing of reactive, carcinogenic intermediates through
direct chemical interaction; (e) inhibition or enhance-
ment of DNA repair mechanisms; and (f ) inhibition
of cell proliferation and DNA synthesis. Specifically,
one may want to choose compounds that act through
one or more different mechanisms (see Table 1). For
example, one may chose an agent that appears to work
primarily by mechanism (a) above, for example,
ellagic acid.2,24 This compound has been shown to
block cytochrome P450 enzymes involved in the
142
metabolic activation of polycyclic aromatic hydro-
carbons. On the other hand, ellagic acid appears to
work also by scavenging electrophilic carcinogenic
intermediates.2,19 Thus, such a compound would fall
into mechanism (d ) above. One may also want to use
proanthocyanidins and green tea polyphenols that fall
into the general class of chemicals that possess antioxi-
dant properties. These compounds have been shown
to alter specific metabolic pathways, including phase I
and phase II enzyme mediated pathways, in bringing
about inhibition of carcinogenesis in different tissues.2,24
All these compounds appear to have the common fea-
ture that they have been shown to induce the activity of
glutathione S-transferases in specific tissues.2,24 Many of
these compounds appear to have actions that would
place them in mechanism (c) above. This latter prop-
erty (that is, the ability to induce enzymes involved in
detoxification of many carcinogens) may represent
the most important property in the ability of some of
these compounds to block carcinogenesis by diverse
carcinogenic agents. Finally, one may choose to use
calcium D-glucarate, an in vivo inhibitor of the β-
glucuronidase enzyme, also involved in detoxification
of many carcinogens and tumor promoters (mecha-
nism (c)).12,13
The process of tumor promotion/progression
involves a combination of several mechanisms.
Among anti-tumor-promoting mechanisms (see
Table 1), the ones that are most promising include (a)
inhibition of inflammation, (b) inhibition of cell pro-
liferation and hyperplasia, (c) modulation of cell dif-
ferentiation and apoptosis, (d) scavenging of reactive
oxygen species and preventing depletion of antioxi-
dant defense systems, and (e) enhancement of tumor
promoter detoxification pathways. The natural cancer-
preventive agents that exert their effects against tumor
promotion usually inhibit one, more, or even all
events involved in the tumor promotion process.2,24,25 It
is unclear, however, whether inhibition of one particu-
lar event involved in promotion by chemopreventive
agents is sufficient and/or necessary to exert their
maximum to complete anti-tumor-promoting
effects.2,25 Specifically, one may chose, for example,
anti-tumor-promoting natural compounds or
extracts2,19 that inhibit inflammation (mechanism (a)
above, agents such as resveratrol and ursolic acid from
rosemary extract); cell proliferation and hyperplasia
(mechanism (b) above, agents such as retinoids and D-
glucarate); and oxygen free radical formation (mech-
anism (d) above, agents such as lycopene and
proanthocyanidins). In addition, one may want to use
novel triterpenoid saponins, named avicins, recently
shown28 to reduce inflammation and hyperplasia
(mechanisms a and b) as well as oxidative damage and
nitrosative stress (mechanism d). Finally, one may use
INTEGRATIVE CANCER THERAPIES 2(2); 2003

Table 1. Targeting Specific Stages of Carcinogenesis With Dietary Factors and Chemopreventive Agents
Mechanisms of Prevention
Tumor Initiation
a. Inhibition of phase I enzymes to prevent the formation of
reactive carcinogenic metabolites
b. Inhibition or induction of oxidative enzyme pathways to
produce less carcinogenic metabolites
c. Enhancement or induction of detoxification enzymes
(phase II enzymes) and pathways
d. Direct chemical scavenging of carcinogenic intermediates
e. Inhibition or enhancement of DNA repair
f. Inhibition of cell proliferation and DNA synthesis
Tumor promotion/progression
a. Inhibition of inflammation
b. Inhibition of cell proliferation and hyperplasia
c. Modulation of cell differentiation and apoptosis
d. Scavenging of reactive oxygen species and preventing
depletion of antioxidant defense systems
e. Detoxification of tumor promoters, especially steroid
hormones
anti-tumor-promoting compounds such as D-
12,13
glucarate to reduce the detrimental effects of free
steroid hormones in the mammary gland and the
prostate gland carcinogenesis (mechanism e). In
breast cancer prevention, D-glucarate may potentially
be used alone or in combination with antiestrogens or
aromatase inhibitors.29
In conclusion, many natural cancer-preventive
agents are effective inhibitors of tumor initiation, pro-
motion, and/or progression. In a number of cases, the
mechanism(s) of action are related to their abilities to
prevent critical carcinogen metabolism, and to
increase detoxification pathways for carcinogens and
free radicals as well as to their antioxidizing activity.
Usually, natural cancer preventive agents inhibit the
initiation and promotion/progression stages to a dif-
ferent degree. Therefore, a combination(s) of various
natural cancer preventive agents, with different mech-
anisms of action, will most likely prove to be more
effective in inhibiting the development of cancer com-
pared to 1 agent. However, one must take into account
that some inducers and inhibitors of phase I, phase II,
and related enzymes may affect the metabolism of can-
cer drugs.30 Making scientifically based decisions30,31
about the use of food and herbal medicines during che-
motherapy is very important because of the critical
nature of cancer treatment.
INTEGRATIVE CANCER THERAPIES X(X); 200X
Detoxifying Cancer Causing Agents
Examples of Preventive Agents/Factors
a. Epigallocatechin gallate (EGCG), selenium, phenylisothiocyanate
(PEITC), indol-3-carbinol, coumarins, ellagic acid, resveratrol,
genistein, 1-ethynylpyrene
b. Butylated hydroanisole (BHA), butylated hydroxytoluene (BHT),
ethoxyquin, 7,8-benzoflavone, quercetin
c. Oltipraz, EGCG, PEITC, diallyl sulfide, resveratrol, N-
acetylcysteine, D-glucarate
d. Ellagic acid
e. Calorie restriction, EGCG, selenium
f. Calorie restriction, difluoromethylornithine, selenium, antiestrogens,
dehydroepiandrosterone (DHEA), fluasterone, retinoids, D-
glucarate
a. Nonsteroidal anti-inflammatory drugs, calorie restriction, DHEA,
fluasterone, antihistamines, resveratrol, ursolic acid, avicins
b. Calorie restriction, difluoromethylornithine, selenium,
antiestrogens, DHEA, fluasterone, retinoids, D-glucarate
c. Retinoids (all-trans retinoic acid, fenretinide), calorie restriction,
monoterpenes (that is, D-limonene), fluasterone, genistein,
calcium
d. Antioxidants (carotenoids, α-tocopherol, ascorbic acid,
proanthocyanidins, EGCG, avicins), selenium, calorie restriction
e. D-Glucarate, aromatase inhibitors, antiestrogens
References
1. Wattenberg LW. Inhibition of carcinogenesis by minor dietary
constituents. Cancer Res. 1992;52:2085s-2091s.
2. Hursting SD, Slaga TJ, Fischer SF, DiGiovanni J, Phang JM.
Mechanism-based cancer prevention approaches: targets,
examples, and the use of transgenic mice. J Natl Cancer Inst.
1999;91:215-225.
3. Dutton GJ. Glucuronidation of Drugs and Other Compounds. Boca
Raton, Fla: CRC Press; 1980.
4. Burchell B, Coughtrie MHW. UDP-Glucuronosyltransferases.
Pharm Ther. 1989;43:261-289.
5. Siest G, Magdalou J, Burchell B. Cellular and Molecular Aspects of
Glucuronidation. Paris: INSERM; 1988.
6. Reddy BS, Weisburger JH, Wynder EL. Fecal bacterial β-
glucuronidase: control by diet. Science. 1974;183:416-417.
7. Levy G, Conchi J. β-Glucuronidase and the hydrolysis of
glucuronides. In: Dutton GJ, ed. Glucuronic Acid: Free and Com-
bined. New York: Academic Press; 1966:301-364.
8. Blumenthal HJ, Lucuta VL, Blumenthal DC. Specific enzymic
assay for D- glucarate in human serum. Anal Biochem.
1990;185:286-293.
9. Colombi A, Maroni M, Antonini C, Fait A, Zocchetti C, Foa V.
Influence of sex, age and smoking habits on the urinary excre-
tion of D-glucaric acid. Clin Chim Acta. 1983;128:349-358.
10. Batt HM, Siest G. Laboratory tests as indirect indications of the
activity of drug metabolizing enzymes: use of glucaric acid and
gamma-glutamyltranspeptidase. Dev Clin Biochem. 1980;2:178-
192.
11. Yokoyama M, Matsuoka S, Wakui A. Activation of tegafur and
urinary excretion of D-glucaric acid in tumor-bearing hosts. In:
Ishigami J, ed. Recent Adv Chemother, Proc Int Congr Chemother,
14th. Tokyo, Japan: University of Tokyo Press; 1985:113-115.
143
 Hanausek et al
12. Walaszek Z. Potential use of D-glucaric acid derivatives in can-
cer prevention. Cancer Lett. 1990;54:1-8.
13. Walaszek Z. Chemopreventive properties of D-glucaric acid
derivatives. Cancer Bull. 1993;45:453-457.
14. Yoshimi N, Walaszek Z, Mori H, Hanausek M, Szemraj J, Slaga
TJ. Inhibition of azoxymethane-induced rat colon carcinogenesis
by potassium hydrogen D-glucarate. Int J Oncol. 2000;16:43-48.
15. Walaszek Z, Szemraj J, Hanausek M, Adams AK, Sherman U. D-
Glucaric acid content of various fruits and vegetables and cho-
lesterol lowering effects of dietary D-glucarate in the rat. Nutr
Res. 1996;16:673-682.
16. Brewster MA. Biomarkers of xenobiotics exposure. Ann Clin
Lab Sci. 1988;18:306-317.
17. Walaszek Z, Hanausek M, Szemraj J, Adams AK. D-Glucaric
acid as a prospective tumor marker. Methods Mol Med.
1998;14:487-495.
18. Walaszek Z, Raich P, Hanausek M, Szemraj J, Narog M, Slaga
TJ. Potential role of D-glucaric acid in lung cancer prevention.
Proc Am Assoc Cancer Res. 2002;43:306.
19. National Research Council; Committee on Diet and Health,
Food and Nutrition Board; Commission on Life Sciences. Diet
and Health: Implications for Reducing Chronic Disease Risk. Wash-
ington, DC: National Academy Press; 1989.
20. Food, Nutrition and the Prevention of Cancer: A Global Perspective.
Washington, DC: World Cancer Research Fund/American
Institute for Cancer Research; 1997.
21. Slaga TJ, O’Connell J, Rotstein J, et al. Critical genetic determi-
nants and molecular events in multistage skin carcinogenesis.
Symp Fundam Cancer Res. 1987;39:31-34.
144
22. DiGiovanni J. Multistage carcinogenesis in mouse skin.
Pharmacol Ther. 1992;47:63-128.
23. Fearon ER, Vogelstein B. A genetic model for colorectal
tumorigenesis. Cell. 1990;61:759-767.
24. Slaga TJ. Inhibition of skin tumor initiation, promotion, and
progression by antioxidants and related compounds. Crit Rev
Food Sci Nutr. 1995;35:51-57.
25. Marks F, Furstenberg G. Cancer chemoprevention through
interruption of multistage carcinogenesis: the lessons learnt
by comparing mouse skin carcinogenesis and human large
bowel cancer. Eur J Cancer. 2000;36:314-329.
26. Bishop JM. Molecular themes in oncogenesis. Cell.
1991;64:235-248.
27. Marshall CJ. Tumor suppressor genes. Cell. 1991;64:313-326.
28. Hanausek M, Ganesh P, Walaszek Z, Slaga TJ, Arntzen C,
Gutterman JU. Avicins, a family of triterpenoid saponins from
Acacia victoriae (Bentham), suppress H-ras mutations and
aneuploidy in a murine skin carcinogenesis model. Proc Natl
Acad Sci U S A. 2001;98:11551-11556.
29. Mokbel K. The evolving role of aromatase inhibitors in breast
cancer. Int J Clin Oncol. 2002;7:279-278.
30. Block KI, Gyllenhaal C. Clinical corner: herb-drug interaction
in cancer chemotherapy: theoretical concerns regarding drug
metabolizing enzymes. Int Cancer Ther. 2002;1:83-89.
31. Lippman SM, Hong WK. Cancer prevention science and prac-
tice. Cancer Res. 2002;62:5119-5125.
INTEGRATIVE CANCER THERAPIES 2(2); 2003