detoxifying cancer causing agents to prevent cancer

7/28/2019 Detoxifying Cancer Causing Agents to Prevent Cancer

1/7

http://ict.sagepub.com/Integrative Cancer Therapies

http://ict.sagepub.com/content/2/2/139The online version of this article can be found at:

DOI: 10.1177/15347354030020020052003 2: 139Integr Cancer Ther

Margaret Hanausek, Zbigniew Walaszek and Thomas J. SlagaDetoxifying Cancer Causing Agents to Prevent Cancer

Published by:

http://www.sagepublications.com

can be found at:Integrative Cancer TherapiesAdditional services and information for

http://ict.sagepub.com/cgi/alertsEmail Alerts:

http://ict.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

http://ict.sagepub.com/content/2/2/139.refs.htmlCitations:

What is This? - Jun 1, 2003Version of Record>>

at Midlands State University on November 19, 2012ict.sagepub.comDownloaded from
http://ict.sagepub.com/http://ict.sagepub.com/http://ict.sagepub.com/http://ict.sagepub.com/content/2/2/139http://ict.sagepub.com/content/2/2/139http://ict.sagepub.com/content/2/2/139http://www.sagepublications.com/http://ict.sagepub.com/cgi/alertshttp://ict.sagepub.com/cgi/alertshttp://ict.sagepub.com/cgi/alertshttp://ict.sagepub.com/subscriptionshttp://ict.sagepub.com/subscriptionshttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsPermissions.navhttp://ict.sagepub.com/content/2/2/139.refs.htmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://ict.sagepub.com/content/2/2/139.full.pdfhttp://ict.sagepub.com/http://ict.sagepub.com/http://ict.sagepub.com/http://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://ict.sagepub.com/content/2/2/139.full.pdfhttp://ict.sagepub.com/content/2/2/139.refs.htmlhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsReprints.navhttp://ict.sagepub.com/subscriptionshttp://ict.sagepub.com/cgi/alertshttp://www.sagepublications.com/http://ict.sagepub.com/content/2/2/139http://ict.sagepub.com/


2/7

10.1177/1534735403253305DetoxifyingCancerCausingAgentsHanauseketal

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, therolesofD-glucaricacid andthe enzyme

-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 -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 andChemoprevention of CancerInhibitionof the induction ofcancer (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 calledblocking agents, whereas those preventing the evolu-tion of the neoplastic process in cells (cancer promo-tion and progression) are called suppressing agents.1

Currently, a number of blocking and suppressingagents are being tested using either pharmacological

or, less often, nutritional regimens. Chemopreventiveblocking agents can prevent the occurrence of cancerby increasing the detoxification of chemical carcino-gens, tumor promoters, and tumor progressors.2 Thepathways of detoxification have been divided into 2major categories: phase I reactions (oxidations,reduc-tions, and hydrolyses) and phase II reactions (conju-

gations). Bothphase I and II reactions are tomake thetoxinmoleculemore polar or water soluble andthere-fore readily excreted.There has been a growing inter-est in the inhibitors that induce an increase in activityof phase II detoxifying enzymes, with a special empha-sis on glutathione S-transferases.2 Glutathione S-trans-ferases conjugate ultimate carcinogens, that is, veryreactive electrophilic metabolites of carcinogeniccompounds, with glutathione.

There is also strong evidence for the detoxificationof chemical carcinogens or their metabolites andtumor promoters/progressors by UDP-glucuronosyl-transferases,2 which conjugate nucleophilic com-

poundsproduced by ourbodies (endogenous)as wellas foreign chemicals (exogenous), with D-glucuronicacid. Conjugation with D-glucuronic acid, that is,glucuronidation, appears to be the principal conjuga-tion pathway in the tissues of all vertebrate speciesexamined to date.3 Theconjugates areexcreted in thebile and urine or transported from one tissue (usuallyliver) to other tissues. UDP-glucuronosyltransferasesare found in the endoplasmic reticulum and nuclearmembranes andaremarkedly inducibleby xenobioticinducers (foreign compounds).4 High specific activityof nuclear UDP-glucuronosyltransferase in thenuclear membrane in proximity to genetic materialsuggests a very important role in the deactivation ofboth foreign and endogenous compoundssuch as ste-roid hormones. Thus, this enzyme could also serve asan important barrier for the nuclear genetic appara-tus against mutagenic and carcinogenic or otherwise

Detoxifying Cancer Causing Agents

INTEGRATIVE CANCER THERAPIES 2(2); 2003 pp. 139-144 139

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:[email protected]: 10.1177/1534735403253305

http://ict.sagepub.com/http://ict.sagepub.com/http://ict.sagepub.com/http://ict.sagepub.com/


3/7

toxic chemical compounds.5 Carcinogens identifiedto date, which after metabolic activation aresubject toglucuronidation, include polycyclic aromatic hydro-carbons, some nitrosoamines, aromatic amines, andfungal toxins. Certain tumor promoters includingste-roid hormones also undergo glucuronidation.3

The importance of conjugating enzymes such asUDP-glucuronosyltransferase, which uses nucleo-philic substrates instead of reactive electrophiles, hasonly recently been recognized.2 It has become appar-ent thatnucleophilic metabolites are often intermedi-ates in formation of ultimate carcinogens. Further-more, it is clear that glucuronidesmay be highlystableforms of these intermediates, which are subject to fur-ther activation after hydrolysis by the enzyme -glucuronidase at sites distant from their site of forma-tion.6 In fact, the elimination and or deactivation ofpotentially damaging chemicals that undergoglucuronidation is limited not only by the rate of con-jugation with D-glucuronic acid but also by the rate ofde-glucuronidation by this ubiquitous enzyme.3

Novel Biomarkers of Detoxification System:D-Glucaric Acid and -Glucuronidase

Theavailabilityof effectivechemoprevention agents isonly one component of a full chemoprevention pro-gram. Another important component is the availabil-ity of a marker or markers that can help evaluate theeffects of chemopreventive agents early during theprevention trials and evaluate individuals as to themagnitude of general or site-specific risk to cancer. Infact, the development of intermediate biomarkers ofcancer risk and theevaluation of efficacy of individualbiological or molecular markers as intermediate endpointsin prevention trialshave been considered as im-portant avenues in cancer research.

Recently, the potential role of the detoxificationsystem and the roles of D-glucaric acid and -glucuronidase in early detection and prevention ofcancer havebeeninvestigated. D-Glucaric acid is a nat-ural, apparently nontoxic compound produced bysome plants, especially in fruits and vegetables, and insmall amounts by mammals, including humans.7 D-

Glucaric acid is an end product of the D-glucuronicacid pathway in mammals.7 Oxidation ofD-glucuronicacid or its lactone leads to oxidation products thathydrolyze spontaneously in aqueous solution to givethe potent -glucuronidase inhibitor, D-glucaro-1,4-lactone, noninhibitory D-glucaro-6,3-lactone, and D-glucaric acid (see Figure 1), all of which are excretedin urine.7 D-Glucaric acid was identified as a normalconstituent of urine7 and serum.8 In fact, D-glucaricacid is a major serum organic acid.8 However, signifi-cant differences in serum levels andurinary excretion

ofD-glucaric acid have been reported8,9 for apparentlyhealthy people. Since urinary excretion ofD-glucaricacid increases following exposure to xenobiotics, itwas suggested for use as an indirect indicator ofhepatic microsomal enzyme induction by xenobioticagents.10 D-Glucaric acid urinary excretion in cancerpatients and tumor-bearing rats was found11 to be sig-nificantly lower than in healthy controls. In mice withexperimental tumors and in cancer patients, unin-volved liver had a lowered D-glucaric acid level.7 Can-

cer tissue itself lacked theD-

glucaric acid synthesizingsystem.7

The physiological function of D-glucaric acid isunclear. Formation ofD-glucaro-1,4-lactone,an inhibi-tor of-glucuronidase, from one of the products of itshydrolytic action (ie, D-glucuronic acid), could beregarded as a negative feedback mechanism. Theaccumulation in the body of free carcinogens, tumorpromoters, and other toxins, normally excreted asglucuronides in the bile or urine, may be aggravatednot only by the elevated -glucuronidase activity butalso by the depressed synthesis of the -glucuronidaseinhibitor 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-glucuronidase, it does enhance net glucuron-idation. Therefore, it has a potential for chemo-prevention of cancer.12,13 There is now growingevidence12-14 from short- and long-term models for thepossiblecontrolof differentstages of thecarcinogenicprocess byD-glucaro-1,4-lactone, and specifically by itsprecursors such as D-glucaric acid salts (D-glucarates).Recently, D-glucaric acid and has been found in somevegetables and fruits.15 Thus, the consumption of

Hanausek et al

140 INTEGRATIVE CANCER THERAPIES 2(2); 2003

HOCH

HCO

HCOH

COOH

HCOH

CO

HOCH

HCOH

HCOH

COOH

HCOH

COOH

OCH

HCO

HCOH

CO

HCOH

CHOH

OCH

HCOH

HCOH

CO

HCOH

COOH

OCH

HCO

HCOH

CO

HCOH

CO

D-Glucurono-6,3-Lactone

D-Glucaro-6,3-Lactone

D-Glucaro-1,4-Lactone

D-Glucaric Acid

Figure 1 In vivo formation of the -glucuronidase inhibitorD-glucaro-1,4-lactone by oxidation of D-glucuronic acidlactone.



4/7

fruits and vegetables naturally rich in D-glucaric acid,

or self-medicationwithD-glucaricacidderivatives suchas calcium D-glucarate or potassium hydrogen D-glucarate, offers a promising chemopreventiveapproach.

The ability to inhibit chemical carcinogenesis byinhibiting -glucuronidase activity has some interest-ingimplications.For example,certain subpopulationsmay be more susceptible to chemical carcinogensbecause of high -glucuronidase activity. There isgood evidence for human subpopulations with highand low-glucuronidase levels. Also, -glucuronidaselevels 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, -glucuronidase activity increases significantly afterboth tobacco smoke exposure and oral tobaccoadministration. 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 associationbetween -glucuronidase activity and chemicalcarcinogenesis in animal models, or cancer incidencein human subpopulations, warrants further study.

Because urinary excretion of D-glucaric acidincreases following exposure to xenobiotics, includ-

ing different toxins and environmental carcinogens,urinary excretion ofD-glucaric acid is considered use-ful as a nonspecific parameter for exposure to envi-ronmental factors.16 In fact, very often, the results ofthe D-glucaric acid tests correlate well with the resultsof bacterial urinary assays for mutagenic activity, thatis,theAmes test.16 Inrelatively smallpopulationstudies,smoking has beenfound tohaveno effect orto cause asignificant increase.9 However, the tobacco use extent,that is, light versus heavy tobacco use, has not beenclearly stated in the above studies. Disease states

known tobeaccompaniedby increasedexcretion ofD-glucaric acid include alcoholism, early stage of renaldisease in children, and liver diseases.16 Decreased val-ues ofD-glucaric acid excretion have been found tooccur in patients with congestive heart failure, starva-tion, severeburns,andfavism.16 However, intraindividual

variations in urinary excretion ofD-glucaric acid havebeen reported.16 Since the total daily urine collectionis often impractical and unreliable, it was proposed todetermine the blood serum levels ofD-glucaric acid incancer patients. It was found17 that normal levels ofD-glucaric acid in theblood serum of healthy people are1.42 0.5 M in women and 1.50 0.29M in men. Incancer patients, the blood serum concentration ofD-glucaric acid drops significantly, that is, to levels usu-ally lower then 1 M.17

Recently, a Phase I clinical trial was undertaken tobegin to explore the potential role ofD-glucaric acidin the prevention of cancer in humans.18 Currentsmokers and nonsmokers, both men and women,were assigned to escalating doses of calcium D-glucarate (from1.5to 9.0gm/day)givenovera 6-weekperiod. Blood levels of D-glucaric acid and -glucuronidase were determined at baseline and every2 weeks.Inaddition, lymphocytesand sputumspecimenswere collected for K-rasoncogene determination. Aconsistent suppression of-glucuronidase levels wasachieved by increasing doses of calcium D-glucarate,which, in turn, correlated well with increasing D-glucaric acid blood levels. DNA was isolated from thelymphocyte fraction of the blood and sputum

obtained from male and female smokers and non-smokers (baseline). Mutated K-ras, an oncogenelinked to lung cancer, was found in the DNA isolatedfrom baseline blood lymphocytes and from sputum ofsome male smokers. NoK-rasmutationswere foundinnonsmokers. The baseline D-glucaric acid level in theblood of smokers with mutated K-raswas significantlylower (ie, by circa 34%, P< .05) than in other smokersor nonsmokers. No unusual toxicity was encounteredin this Phase I study, and calcium D-glucarate was welltolerated, even at the highest dose levels.18 Thus, cal-cium D-glucarate supplementation has potential forreducing the risk of lung cancer development in

tobacco smokers. The results of extensive animalstudies12,13 also suggest that calcium D-glucarate mayreduce the risk of lung as well as breast, prostate, liver,skin, and colon cancer in humans.

Importance of NaturalInhibitors of Carcinogenesis

Scores of epidemiologic studies have noted a lowerrisk of canceramong persons whose diet include a rel-atively large amount of vegetables, fruits, and other


INTEGRATIVE CANCER THERAPIES 2(2); 2003 141

Figure 2 The effect of calcium D-glucarate and D-glucaro-1,4-lactone on detoxification of compounds that undergoglucuronidation.



5/7

plant products.19,20A popular explanation, both withinthe scientific community and among members of thepublic, is thatdifferentvitaminsandother micronutri-ents invegetables, fruits, andothernaturalplantprod-ucts prevent carcinogenesis by interfering withdetrimental actions of mutagens, carcinogens, and tu-

mor promoters. These natural inhibitors of carcino-genesis areapparently nontoxicor markedly less toxicthan synthetic chemopreventive agents. Although it isgenerally accepted that a diet of large amounts of veg-etables, fruits, and other plant products lowers cancerincidence, there is still a need to identify the most ef-fective constituents of the diet as well as to elucidatetheir mechanisms of action.

There has been significant progress in the under-standing of the multistage nature of carcinogenesis21-23

and the mechanisms of cancer prevention.2,24,25 Themouse skin model, which represents one of the bestunderstood experimental models of multistage

carcinogenesis, has permitted the resolution of threedistinct stages: initiation, promotion, and progres-sion.21,22 It is now apparent that the cellular evolutionto malignancy involves the sequential alteration ofproto-oncogenes 26 and/or tumor suppressor genes,27

whose gene products participated in critical pathwaysfor the transduction of signals and/or regulation ofgene expression.

One of the goals of current studies in cancer pre-vention is to determine the mechanisms of synergisticaction of the natural source compounds, known toinhibit one or more stages of carcinogenesis, that is,

initiation and promotion/progression.

2,24

The basictheory underlying these studies is that concurrenttreatment withvarious natural source inhibitors of dif-ferent stages of carcinogenesis results in synergisticeffects, leadingto moreefficient prevention ofcancer.

The mechanisms that focus on initiation eventsinclude (a) inhibition oralteration ofphase I enzymesresponsible for the formation of reactive carcinogenicmetabolitesultimately leading to their reduced forma-tion; (b) inhibition or induction of oxidative enzymepathwaysthatproduce productsof lower carcinogenicpotential; (c) induction of detoxification enzymes(phase II enzymes) and pathways (nonoxidative) for

bothproximate andultimate carcinogen; (d) scaveng-ing of reactive, carcinogenic intermediates throughdirect chemicalinteraction;(e) inhibition orenhance-ment of DNA repair mechanisms; and (f) inhibitionof cell proliferation and DNA synthesis. Specifically,one may want to choose compounds that act throughone or more different mechanisms (see Table 1). Forexample,onemay chose anagent that appears toworkprimarily by mechanism (a) above, for example,ellagic acid.2,24 This compound has been shown toblock cytochrome P450 enzymes involved in the

metabolic activation of polycyclic aromatic hydro-carbons. On the other hand, ellagic acid appears towork also by scavenging electrophilic carcinogenicintermediates.2,19 Thus, such a compound would fallinto mechanism (d) above. One may also want to useproanthocyanidinsand greentea polyphenols thatfall

into thegeneral class ofchemicalsthat possess antioxi-dant properties. These compounds have been shownto alter specific metabolic pathways, includingphase Iand phase II enzyme mediated pathways, in bringingabout 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 activityofglutathione S-transferases in specific tissues.2,24 Many ofthese compounds appear to have actions that wouldplace them in mechanism (c) above. This latter prop-erty (that is, the ability to induce enzymes involved indetoxification of many carcinogens) may representthe most important property in the ability of some of

these compounds to block carcinogenesis by diversecarcinogenic agents. Finally, one may choose to usecalcium D-glucarate, an in vivo inhibitor of the -glucuronidase enzyme, also involved in detoxificationof many carcinogens and tumor promoters (mecha-nism (c)).12,13

The process of tumor promotion/progressioninvolves a combination of several mechanisms.Among anti-tumor-promoting mechanisms (seeTable 1), theones that aremost promisinginclude (a)inhibition of inflammation, (b) inhibition of cell pro-liferation and hyperplasia, (c) modulation of cell dif-

ferentiation and apoptosis, (d) scavenging of reactiveoxygen species and preventing depletion of antioxi-dant defense systems, and (e) enhancement of tumorpromoter detoxification pathways. The natural cancer-preventive agents thatexert their effects against tumorpromotion usually inhibit one, more, or even allevents involvedin the tumor promotion process.2,24,25 Itis unclear, however, whether inhibition of one particu-lar event involved in promotion by chemopreventiveagents is sufficient and/or necessary to exert theirmaximum to complete anti-tumor-promotingeffects.2,25 Specifically, one may chose, for example,anti-tumor-promoting natural compounds or

extracts2,19

that inhibit inflammation (mechanism (a)above,agentssuch as resveratrol and ursolic acid fromrosemary 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 andproanthocyanidins). In addition, one may want to usenovel triterpenoid saponins, named avicins, recentlyshown28 to reduce inflammation and hyperplasia(mechanismsaand b) as well as oxidative damage andnitrosative stress (mechanism d). Finally, one may use

Hanausek et al




6/7

anti-tumor-promoting compounds such as D-glucarate12,13 to reduce the detrimental effects of freesteroid hormones in the mammary gland and theprostate gland carcinogenesis (mechanism e). In

breast cancer prevention, D-glucarate may potentiallybe used alone or in combination with antiestrogens oraromatase inhibitors.29

In conclusion, many natural cancer-preventiveagents areeffective inhibitors of tumor initiation, pro-motion, and/or progression.In a number ofcases, themechanism(s)of actionarerelated to their abilities toprevent critical carcinogen metabolism, and toincrease detoxification pathways for carcinogens andfree radicals as well as to their antioxidizing activity.Usually, natural cancer preventive agents inhibit theinitiation and promotion/progression stages to a dif-ferent degree. Therefore,a combination(s) of various

natural cancer preventive agents,withdifferentmech-anisms of action, will most likely prove to be moreeffectivein inhibiting thedevelopment of cancer com-pared to1 agent. However, one must take into accountthat some inducers and inhibitors of phase I, phase II,andrelatedenzymes mayaffect themetabolismofcan-cer drugs.30 Making scientifically based decisions30,31

about the useof food and herbal medicines during che-motherapy is very important because of the criticalnature of cancer treatment.

References1. Wattenberg LW. Inhibition of carcinogenesisby minordietary

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. BocaRaton, Fla: CRC Press; 1980.

4. Burchell B, Coughtrie MHW. UDP-Glucuronosyltransferases.Pharm Ther. 1989;43:261-289.

5. Siest G,Magdalou J, BurchellB. Cellular and Molecular Aspects ofGlucuronidation. Paris: INSERM; 1988.

6. Reddy BS, Weisburger JH, Wynder EL. Fecal bacterial -glucuronidase: control by diet. Science. 1974;183:416-417.

7. Levy G, Conchi J. -Glucuronidase and the hydrolysis ofglucuronides. 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 enzymicassay 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, ageand smoking habitson theurinaryexcre-tion ofD-glucaric acid. Clin Chim Acta. 1983;128:349-358.

10. Batt HM,SiestG. Laboratory tests as indirect indicationsof theactivity of drug metabolizingenzymes: useof glucaric acid andgamma-glutamyltranspeptidase.Dev Clin Biochem. 1980;2:178-192.

11. Yokoyama M, Matsuoka S, Wakui A. Activation of tegafur andurinary excretionofD-glucaricacidin tumor-bearing hosts.In:Ishigami J, ed. Recent Adv Chemother, Proc Int Congr Chemother,14th. Tokyo, Japan: University of Tokyo Press; 1985:113-115.


INTEGRATIVE CANCER THERAPIES X(X); 200X 143

Table 1. Targeting Specific Stages of Carcinogenesis With Dietary Factors and Chemopreventive Agents

Mechanisms of Prevention Examples of Preventive Agents/Factors

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

a. Epigallocatechin gallate (EGCG), selenium, phenylisothiocyanate

(PEITC), indol-3-carbinol, coumarins, ellagic acid, resveratrol,

genistein, 1-ethynylpyrene

b. Butylatedhydroanisole (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

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

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-transretinoic acid, fenretinide), calorie restriction,

monoterpenes (that is, D-limonene), fluasterone, genistein,

calciumd. Antioxidants (carotenoids, -tocopherol, ascorbic acid,

proanthocyanidins, EGCG, avicins), selenium, calorie restriction

e. D-Glucarate, aromatase inhibitors, antiestrogens



7/7

12. Walaszek Z. Potential use ofD-glucaric acid derivatives in can-cer prevention. Cancer Lett. 1990;54:1-8.

13. Walaszek Z. Chemopreventive properties of D-glucaric acidderivatives. Cancer Bull. 1993;45:453-457.

14. Yoshimi N, Walaszek Z, Mori H, Hanausek M, Szemraj J, SlagaTJ. Inhibitionof azoxymethane-inducedratcoloncarcinogenesisby potassiumhydrogen D-glucarate.IntJ Oncol. 2000;16:43-48.

15. WalaszekZ, Szemraj J, HanausekM, Adams AK,Sherman U.D-

Glucaric acid content of various fruits and vegetables andcho-lesterol lowering effects of dietaryD-glucarate in the rat. NutrRes. 1996;16:673-682.

16. Brewster MA. Biomarkers of xenobiotics exposure. Ann ClinLab Sci. 1988;18:306-317.

17. Walaszek Z, Hanausek M, Szemraj J, Adams AK. D-Glucaricacid as a prospective tumor marker. Methods Mol Med.1998;14:487-495.

18. Walaszek Z, Raich P, Hanausek M, Szemraj J, Narog M, SlagaTJ. Potential role ofD-glucaric acid in lungcancer 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. Dietand 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/AmericanInstitute for Cancer Research; 1997.

21. SlagaTJ, OConnellJ, RotsteinJ, etal. Criticalgeneticdetermi-nants and molecular events in multistage skin carcinogenesis.Symp Fundam Cancer Res. 1987;39:31-34.

22. DiGiovanni J. Multistage carcinogenesis in mouse skin.Pharmacol Ther. 1992;47:63-128.

23. Fearon ER, Vogelstein B. A genetic model for colorectaltumorigenesis. Cell. 1990;61:759-767.

24. Slaga TJ. Inhibition of skin tumor initiation, promotion, andprogression by antioxidants and related compounds. Crit RevFood Sci Nutr. 1995;35:51-57.

25. Marks F, Furstenberg G. Cancer chemoprevention throughinterruption of multistage carcinogenesis: the lessons learntby comparing mouse skin carcinogenesis and human largebowel 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 fromAcacia victoriae (Bentham), suppress H-ras mutations andaneuploidy in a murine skin carcinogenesis model. Proc NatlAcad Sci U S A. 2001;98:11551-11556.

29. Mokbel K. The evolving role of aromatase inhibitors in breastcancer. Int J Clin Oncol. 2002;7:279-278.

30. Block KI, Gyllenhaal C. Clinical corner: herb-drug interactionin cancer chemotherapy: theoretical concerns regarding drug

metabolizing enzymes. Int Cancer Ther. 2002;1:83-89.31. Lippman SM,Hong WK.Cancer prevention science andprac-

tice. Cancer Res. 2002;62:5119-5125.

Hanausek et al


S

detoxifying cancer causing agents to prevent cancer

Documents