Mutation Research 402 1998.

151158

Mechanisms of inhibitors of mutagenesis and carcinogenesis

Silvio De Flora

Institute of Hygiene and Preentie Medicine, Uniersity of Genoa, ia A. Pastore 1, I-16132 Genoa, Italy
Received 17 April 1997; accepted 1 July 1997

Abstract
For a rational implementation of chemoprevention strategies it is essential not only to assess the efficacy and safety of
putative inhibitors by using a variety of test systems but also to understand the mechanisms involved. This article proposes a
detailed classification of mechanisms along with pertinent examples of agents which may be potentially exploited in the
host-addressed prevention of cancer and other mutation-related diseases. The classification, presented in tabulated form,
covers a variety of mechanisms interfering with different phases of mutagenesis and carcinogenesis. However, the reported
sequence of events is not meant to follow a rigid scheme, and several mechanisms are reiterated throughout evolution of
these processes. Similarly, a number of protective agents are shown to work through multiple and often interconnected
mechanisms. q 1998 Elsevier Science B.V. All rights reserved.
Keywords: Antimutagenesis; Anticarcinogenesis; Mechanism; Inhibitor; Chemoprevention

1. Introduction
There is increasing evidence that mutations in
somatic cells are not only involved in the carcinogenesis process but do also play a role in the pathogenesis of other chronic degenerative diseases, such
as atherosclerosis and heart diseases, which are the
leading causes of death in the human population w1x.
In spite of the multiplicity and clinical diversity of
these diseases, certain conditions are associated with
common risk factors as well as with common protective factors, and in addition they share common
pathogenetic determinants, such as genotoxic events
or oxidative stress w1x.
)
Corresponding author. Tel.: q39-10-353.8500; fax: q39-10353.8504; E-mail: sdf@unige.it

Prevention of cancer and other mutation-related

diseases can be pursued both by avoiding exposures
to recognized mutagensrcarcinogens and by favoring the intake of protective factors or fortifying
physiological defense mechanisms. The latter approach, referred to as chemoprevention, is extremely
delicate since it involves dietary or pharmacological
intervention in the host organism. Therefore, its application is only feasible on the basis of careful
riskbenefit analyses evaluating the safety of protective agents and their efficacy, as assessed in a variety
of test systems from in vitro and in vivo experimental models to clinical trials w2,3x. Furthermore, it is
essential to establish the mechanisms. of action of
putative inhibitors w4x. Accordingly, studies in this
area of preventive medicine should be designed in
order to evaluate efficacy and safety of candidate

0027-5107r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.

PII S 0 0 2 7 - 5 1 0 7 9 7 . 0 0 2 9 2 - 3

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S. De Flora r Mutation Research 402 (1998) 151158

chemopreventive agents as well as the mechanisms

underlying their modulating activity.
As a preliminary consideration to an overview of
mechanisms it should be noted that it is often difficult to discriminate individual mechanisms and also
to distinguish whether modulation of a given endpoint is actually a specific mechanism or rather the
epiphenomenon of other mechanisms. For instance,
inhibition of formation of adducts to either nuclear
DNA or mitochondrial DNA, rather than a mechanism, is a biomarker which reflects the occurrence of
protective mechanisms preceding the binding of electrophilic molecules to DNA w5x. As a further example, induction of apoptosis is a mechanism by which
certain chemopreventive agents affect the survival of
damaged cells see Table 1, mechanism 3.6.. However, other chemopreventive agents may be found to
inhibit cell apoptosis simply because they work upstream in the chain of events which ultimately trigger the apoptotic phenomenon.

2. Classification of mechanisms of inhibitors

Table 1 reports a detailed classification of mechanisms of inhibitors of mutagenesis and carcinogenesis, which revises and updates previous proposals w4,611x. This scheme takes into account the
multiple phases involved in the pathogenesis of cancer and other mutation-related diseases. The classification analyzes first the inhibition of mutation and of
cancer initiation, either extracellularly or inside cells,
and then the mechanisms interfering with later stages
of carcinogenesis, i.e., promotion, progression, invasion, and metastasis. It should be noted that an
initiationpromotion sequence has been also postulated to occur in the pathogenesis of other chronic
degenerative diseases, such as atherosclerosis and
juvenile diabetes w12x. This diphasic process can be
reproduced in animal models for the development
not only of tumors but also of atherosclerotic plaques
w13x. According to Wattenberg w14x, chemopreventive
agents can be placed in two major categories, i.e.,
blocking agents, which prevent carcinogens from
reaching or reacting with critical target sites, and
suppressing agents, which prevent the evolution of
the neoplastic process. Blocking agents are inhibitors
of tumor initiation, while suppressing agents can be

identified with inhibitors of promotionrprogression

w15x. The ICPEMC Expert Group on Antimutagens
and Desmutagens made a distinction between stage-1
inhibitors, acting extracellularly, and stage-2 inhibitors, acting intracellularly w16x. Antimutagens
were categorized by Kada et al. w17x into desmutagens, which inactivate mutagens before they can
attack DNA, and bioantimutagens, which interfere
with fixation of DNA damage.
Actually, multiple genetic changes have been
shown to occur along all stages of carcinogenesis
w18x, and development of cancer has alternatively
been viewed as a continuum of mutagenic and mitogenic events, which does not fit a rigid scheme
covering multiple, separate phases w19x. Accordingly,
some classifications of cancer chemopreventive
agents distinguish inhibitors based on their intervention level throughout the process leading from a
normal cell to an initiated cell, and then to dysplasia
of increasing severity up to carcinoma in situ, and
ultimately to cancer w3,2022x. Indeed, 10 years ago
De Flora and Ramel w4x already pointed out that the
sequence of events occurring during the carcinogenesis process . . . should not be oversimplified by
any rigid classification into definite steps involved in
the initiationpromotionprogression operative
scheme. These concepts are taken into account in
the classification proposed in Table 1, in which the
cascade of mechanisms should be interpreted in a
flexible way, and several mechanisms e.g., inhibition of genotoxic effects, antioxidant activity and
scavenging of free radicals, inhibition of cell proliferation, induction of cell differentiation, signal transduction modulation, etc.. are reiterated several times
in different phases of the process. It is also clear that
certain mechanisms are strictly interconnected or
partially overlapping.
Apart from the fact that some physical or mechanical means are also included, the bulk of the classification shown in Table 1 mechanisms 14. is mostly
coincident with a classification of chemopreventive
agents. Cancer chemoprevention can be defined as
the inhibition or reversal of carcinogenesis at a premalignant stage w20x. Therefore, chemoprevention
falls within primary prevention inhibition of occurrence of a disease. when it is addressed to healthy
individuals, and within secondary prevention early
diagnosis, possibly in a preclinical stage, followed

S. De Flora r Mutation Research 402 (1998) 151158

153

Table 1
Mechanisms and examples of agents protecting the organism from mutagens and carcinogens, potentially exploitable in the prevention of
cancer and other mutation-related diseases
Mechanisms
1. Extracellular mechanisms
1.1. Inhibition of uptake of mutagensrcarcinogens
1.1.1. Inhibition of penetration

1.1.2. Removal from the organism

1.2. Inhibition of the endogenous formation of mutagens and
carcinogens
1.2.1. Inhibition of nitrosation

1.2.2. Modification of the intestinal microbial flora

1.3. Complexation, dilution andror deactivation of

mutagensrcarcinogens
1.3.1. By physical or mechanical means

1.3.2. By chemical reaction or enzyme-catalyzed reaction

1.4. Favoring absorption of protective agents

2. Inhibition of mutation and cancer initiation by cellular
mechanisms
2.1. Stimulation of trapping and detoxification in nontarget cells
2.2. Modification of transmembrane transport
2.2.1. Inhibition of cellular uptake

2.2.2. Stimulation of extrusion outside cells

2.3. Modulation of metabolism
2.3.1. Inhibition of activation of promutagensrprocarcinogens by Phase I

2.3.2. Induction of Phase I detoxification and Phase II

conjugation pathways, or acceleration of decomposition
of reactive metabolites

Examples

Body shielding devices, sun-protecting creams, washing and mechanical removal from the skin, oral mucosa and genital mucosa,
restoration with drugs of impaired physiological mechanisms e.g., the
muco-ciliatory escalator. w4,9x; oral vaccines stimulating secretory
IgA against carcinogens w8,9x; dietary calcium w3,8x
Dietary fibers w4,8x

Vitamins ascorbic acid, a-tocopherol., sulfur compounds bisulfite,

cysteine, GSH, NAC, methionine, sulfamic acid., phenols catechol,
cinnamic acid, chlorogenic acid, gallic acid, hydroquinones, phenolic
acids, pyrogallol, tannic acid, tannins, thymol, BHA, BHT., food
extracts and beverages w8,24x
Fermented dairy products, precursors of GSH in intestinal bacteria
NAC. w4,8x; inhibition of conversion of lipids to DAG calcium. w21x

Maintenance of physiological pH in body fluids, dietary fibers w4,8x;

magnesium hydroxide w25x
Calcium, oleic acid, C16C24 unsaturated fatty acids, vegetables with
peroxidase or NADPH-oxidase activities w8x; trapping agents see
2.4.1.; antioxidants see 2.4.2.
Vitamin D3 and analogues w21x

NAC in erythrocytes and pulmonary alveolar macrophages. w4,8x

Short-chain fatty acids caproate, caprylate., putrescine, iodide,

aromatic amino acids w4,8x; acylglycosylsterols, dietary calcium w9x
Possible modulators of MDR mechanism w9x

Principles of cruciferous plants phenols, arylalkyl isothiocyanates,

indoles, dithiol-enzymes thiones., monocyclic monoterpenoids Dlimonene, menthol and carveol., retinoids, flavonoids, nicotinamide,
short-chain saturated fatty acids laurate., hemin w8x; chlorophyllin
w26x; NADPH depletors DHEA, fluasterone. w21x; disulfiram w16x;
diethyldithiocarbamate w22x; b-carotene w3x
Oltipraz and other dithiolthiones, natural and synthetic phenols, NAC,
X
indoles, isothiocyanates, diterpene esters, riboflavin 5 -phosphate w8x;
S-allyl-L-cysteine w21x; allylic sulfides w22x

S. De Flora r Mutation Research 402 (1998) 151158

154
Table 1 continued.
Mechanisms

2.3.3. Stimulation of activation, coordinated with detoxification and trapping of reactive metabolites
2.4. Blocking or competition
2.4.1. Trapping of electrophiles by either chemical reaction
or enzyme-catalyzed conjugation

Examples
NAC, indole-3-carbinol w8,9x

NAC and other thiols, oltipraz, sodium thiosulfate, diallyl sulfide,

ergothioneine, polyphenols flavonoids, tannins, ellagic acid., creatinine, nicotinamide w8x; hemin, chlorophyllin w27x; magnesium ions
w25x

2.4.2. Antioxidant activity and scavenging of reactive oxygen

species

Provitamins and vitamins b-carotene, ascorbic acid, a-tocopherol.,

selenium, chymotrypsin-specific protease inhibitor, thioproline, ergothioneine w8x; uric acid w26x; diterpenes sarcophytol A. w15x;
polyphenols, flavonoids, NAC and other thiols, NSAIDs aspirin,
ibuprofen, indomethacin, piroxicam., glycyrrhetinic acid, tamoxifen
w22x; inhibitors of prostaglandin E2 synthesis eicosapentaenoic acid.
w28x; inducers of antioxidant enzymes PSK-1, bismuth nitrate. w3x

2.4.3. Protection of DNA nucleophilic sites

Ellagic acid, retinoids w4,8x; polyamines w29x

2.5. Inhibition of cell replication

2.6. Modulation of DNA metabolism and repair

2.6.1. Increase of fidelity of DNA replication and repair

Retinoids, glucocorticoids, isothiocyanates, local hyperthermia w4,8x;

deltanoids, NSAIDs w3x; inhibitors of ODC activity or of its induction
DFMO w21x; MGBB w30x., inorganic and organic selenium compounds, calcium, DHEA, fluasterone w21x; inositol hexaphosphate
w31x; tamoxifen w22x

Cobaltous chloride, sodium arsenite w4,8x; magnesium w25x; inhibitors

of topoisomerases I camptothecin w32x. and II genistein w21x.

2.6.2. Stimulation of repair andror reversion of DNA

damage

Cinnamaldehyde, coumarin, vanillin, umbelliferone, tannic acid,

PARP protectors NAC. w4,8x

2.6.3. Inhibition of error-prone repair

Protease inhibitors, PABA w8x

2.6.4. Correction of hypomethylation

Folic acid, methionine, SAM w21x

2.7. Control of gene expression

2.7.1. Inhibition of oncogene expression

2.7.2. Inhibition of oncogene sequences

2.7.2.1. Inhibition of translation targeted to oncogene
mRNA

SAM, retinoids, inhibitors of gene amplification protease inhibitors.

w8x; calcium, lovastatin, D-limonene w21x

Antisense oligonucleotides e.g., myc, myb, bcl2, abl, ras . w33x

2.7.2.2. Inhibition of transcription of specific DNA

sequences

Antigene oligonucleotides e.g., myc, ras . w33x

2.7.2.3. Site-specific DNA binding

Proteins binding oncogene sequences w34x

2.7.3. Neutralization of oncogene products

Antibodies towards oncoprotein amino acids w4x; drugs interfering

with the cholesterol biosynthetic pathway and inhibiting activated
c-H-ras oncoprotein w8,21x

2.7.4. Replacement of deleted tumor suppressor genes

Whole chromosome transfer or gene transfer w7,22x

2.7.5. Killing of cells lacking tumor suppressor genes

Mutant adenovirus replicating in p53-deficient human cells w35x

S. De Flora r Mutation Research 402 (1998) 151158

155

Table 1 continued.
Mechanisms

Examples

3. Inhibition of tumor promotion

3.1. Inhibition of genotoxic effects

See 1 and 2

3.2. Antioxidant activity and scavenging of free radicals

See 2.4.2

3.3. Inhibition of proteases

A variety of protease inhibitors w8,21x

3.4. Inhibition of cell proliferation

See 2.5

3.5. Induction of cell differentiation

Retinoids, calcium, glucocorticoids w4x; deltanoids w21x; hexamethylene bisacetamide, 1-b-D-arabinofuranosyl-cytosine, 5-azacytidine w36x

3.6. Induction of cell apoptosis

Retinoids, sulindac sulfone, tamoxifen, butyric acid, genistein w22x;

flavonoids w37x

3.7. Protection of intercellular communications

b-carotene, canthaxanthine, vitamin A and retinoids w22x

3.8. Signal transduction modulation

PKC inhibitors tamoxifen, glycyrrhetinic acid, staurosporine, genistein, retinoids, sphingosines, selenium, dibucaine, verapamil, trifluoperazine, doxorubicin, polyamines, flavonoids. w4,21,22,38x; PKA
inhibitors 8-Cl cyclic AMP. w39x; farnesylation inhibitors Dlimonene, DHEA, perillyl alcohol, nerolidol., NSAIDS w3,21,22x

4. Inhibition of tumor progression

4.1. Inhibition of genotoxic effects

See 1 and 2

4.2. Antioxidant activity and scavenging of free radicals

See 2.4.2

4.3. Inhibition of proteases

See 3.3

4.4. Signal transduction modulation

See 3.8

4.5. Effects on the hormonal status

Tamoxifen, toremifene, genistein w22x; aromatase inhibitors 4-hydroxyandrost-4-ene-3,17-dione, q.-vorozole w22x; CGS 18320b w3x.,
inducers of estradiol 2-hydroxylation indole-3-carbinol. w3x; oral
contraceptives, 5 a-reductase inhibitors finasteride. w40x; dopamine
antagonists w4x

4.6. Effects on the immune system

Vaccination with tumor-specific antigens and specific anti-idiotypic

antibodies w41x; a-tocopherol, retinoids, selenium w22x; lipotropes
choline, folate, methionine, vitamin B12. w37x

4.7. Inhibition of neovascularization

Retinoids, tamoxifen w22x; genistein w21x; thiols NAC. w42x; angiostatic steroids, interferons, cytokines, chemokines, inhibitors of
collagene metabolism proline analogues., antibiotics, fumagillin,
linomide, TNP470, heparinoids, suramine, protamine sulphone,
chemotherapeutics methotrexate, mitoxanthrone, bisanthrene., inhibitors of tyrosine kinase growth factor receptors w43x; inhibitors of
serino proteinases PAI-1. w44x; inhibitors of metalloproteinases see
5.1.; PKC inhibitors see 3.8.

4.8. Physical, chemical, or biological antineoplastic activity

Radiation, cytostatic drugs, interferon w4x; preventive surgery of

benign tumors

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S. De Flora r Mutation Research 402 (1998) 151158

Table 1 continued.
Mechanisms

Examples

5. Inhibition of inasion and metastasis

5.1. Inhibition of proteases involved in basement membrane
degradation and modulation of the interaction with the
extracellular matrix

Retinoids w21x; protease inhibitors, cathepsin B w22x; NAC w45x;

TIMP-1, TIMP-2, batimastat, marimastat, -aminocaproic acid,
polyphenols, eicosapentaenoic acid, hydroxamic acid w46x

5.2. Induction of cell differentiation

See 3.5

5.3. Inhibition of neovascularization

See 4.8

5.4. Effect on cell-adhesion molecules

Inhibitors of integrins w43x

5.5. Antioxidant activity

See 2.4.2

5.6. Signal transduction modulation

See 3.8

5.7. Activation of antimetastasis genes

Enhancement of immunogenicity of tumor cells by insertion of genes

encoding MHC-HLA andror cytokines w47x

Abbreviations: BHA, butylated hydroxytoluene; BHT, butylated hydroxyanisole; DAG, diacylglycerol; DFMO, a-difluoromethylornithine;
DHEA, dehydroepiandrosterone; EGFR, epidermal growth factor; GSH, reduced glutathione; MDR, multidrug resistance; MGBB,
methylglyoxal bisbutylamidinohydrazone.; MHC-HLA, major histocompatibility complex-human leukocyte locus A; NAC, N-acetyl-L-cysteine; NSAIDs, nonsteroidal antiinflammatory drugs; ODC, ornithine decarboxylase; PABA, para-aminobenzoic acid; PAI-1, plasminogen
activator inhibitor; PARP, polyADP-ribose. polymerase; PKA, protein kinase A; PKC, protein kinase C; SAM, S-adenosyl-L-methionine;
TIMP, tissue inhibitor of metalloproteinases.

by timely intervention. when it is addressed to individuals suffering from a preneoplastic situation in

order to achieve its regression. Prevention of multiple primary tumors also falls within secondary prevention, since these tumors are expected to be in an
advanced, preclinical stage at the time of intervention. Inhibition of invasion and metastasis mechanisms 5.15.8. is conversely outside the boundary of
chemoprevention, and falls within so-called tertiary
prevention w5x.

3. Examples of protective agents based on their

mechanisms
The list of examples reported in Table 1 includes
both natural and synthetic agents, often represented
by food components or by drugs, some of which
have been extensively used for a variety of therapeutical purposes. This list is far from being complete,
and does not pretend to cover the huge literature
exhaustively dealing with mechanisms of inhibitors.
Due to limitations in space, whenever possible the
examples of inhibitors were referenced with review

articles, and only in particular cases individual studies were cited. I refer to the reported articles and to
the therein cited references for more details and for
pointing out the original studies highlighting each
mechanism.
As previously discussed w4,8x, it has become an
important issue that many inhibitors are known or
suspected to work through multiple mechanisms,
which are likely to render these inhibitors more
effective towards a broader range of carcinogens and
at risk situations. The multiplicity of mechanisms of
certain agents can at least in part be inferred from
the reported series of examples. It is also noteworthy
that interactions may occur between different inhibitors available in nature, e.g., in certain foods w8x.
Complementary mechanisms can be exploited in socalled combined chemoprevention w3,23x.

4. Conclusions
It is evident that some of the mechanisms reported
in Table 1 are just hypothetical or, at least so far, of
preminent academic interest. Conversely, other

S. De Flora r Mutation Research 402 (1998) 151158

mechanisms and agents deserve practical applications, for the time being or in the near future, and
may be considered either for public health interventions addressed to the general population or for
target chemoprevention in high risk categories. These
categories include heavily exposed individuals as
well as individuals having a particularly high susceptibility to mutagens and carcinogens due to metabolic
polymorphisms, DNA repair deficiencies, or impairment of tumor suppressor genes.
Acknowledgements
Preparation of this article was supported by the
Italian Ministry of University and ScientificTechnological Research MURST, 40% and 60% grants..
I thank Drs. A. Albini and M. Bagnasco for critical
discussion and helpful suggestions.
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