Page 375 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

342 SECTION | III Nanoparticles, Radiation and Carcinogens

VetBooks.ir assumed to have a risk and the higher the exposure the TABLE 20.3 Examples on the Mechanism of Action of
greater the risk. In contrast, nongenotoxic carcinogens are
Two Tumor Initiators
assumed to produce nonlinear dose-response curve.
Therefore, nongenotoxic carcinogens are assumed to have a DMBA forms DNA adduct by covalently binding through its
threshold of exposure below which tumor development is 12-methyl group to the N-7 position of adenine (major
not expected. adduct) or guanine (minor adduct). Removal of the N-7
purine adducts leads to depurination and mutation. If the
mutation involves an oncogene or a tumor suppressor gene,
Carcinogenesis Is a Multistep Biological such as A-T transversion in ras oncogene, the result could
Process That Involves Three Major Events: be disastrous
Initiation, Promotion, and Progression N-methyl-N-nitrosourea (MNU) forms DNA adduct by
6
modifying guanine to O -methylguanine in the target tissue.
The three distinct steps of chemical carcinogenesis are ini- The ‘suicide enzyme’ O -methylguanine-DNA
6
tiation, promotion, and progression (Foulds, 1954). Based methyltransferase (MGMT) repairs this lesion. It is called
on the experimental data, Isaac Berenblum and Philippe suicide enzyme because following repair the enzyme is
inactivated because Cys145 residue in the active site of
Shubik (1947) first proposed the two-stage “initiationa 6
MGMT binds the methyl group removed by the O -
promotion model” of carcinogenesis. The term “progression” 6
methylguanine. Unrepaired O -methylguanine lesion leads to
was later added as a distinct step by Leslie Foulds, G-A transition. Transgenic mice overexpressing MGMT are
although the concept of progression of cancer had already less sensitive to tumor development in the tissue
been articulated by Peyton Rous and others (Foulds, 1954). overexpressing the enzyme. Methyl group is the preferred
substrate of MGMT, but it can remove larger and complex
alkyl groups, which makes MGMT an alkyltransferase
Tumor Initiation Is an Irreversible Genetic Event
That Produces Preneoplastic Cells
The chemical causing initiation is called an initiator. In the
initiation phase, the chemical or its reactive metabolite
causes a permanent change in the DNA of the target cell(s), TABLE 20.4 Examples of Tumor Initiators, Promoters,
such as a mutation, a distortion of the DNA structure with and Progression Agents
further consequences, deletion of a component of DNA Tumor initiators Benzo[a]pyrene
(bases or sugars), or errors in DNA repair (Pitot, 2002). 7,12-dimethylbenz[a]anthracene
Thus, initiation is a genetic event. If the DNA damage is (DMBA)
N-methyl-N-nitrosourea (MNU)
not repaired or the cell containing the damage does not
3-methylcholanthrene
undergo apoptosis, the damage is fixed in the cellular
2-acetylaminofluorene
genome and the target cell is initiated. From this point on Dimethylnitrosamine
initiation is irreversible. An initiated cell is preneoplastic Diethylnitrosamine
and by itself is not a cancer cell because it has not acquired Tumor TPA (12-O-tetradecanoylphorbol-13-
the property of uncontrolled growth. In order for an initi- promoters acetate, a phorbol ester isolated from
ated cell to transform into a cancer cell and eventually pro- croton oil) is skin-specific
duce a detectable tumor, promotion is necessary. Chlordane, DDT
(dichlorodiphenyltrichloroethane),
In 1971 Alfred Knudson proposed the two-hit hypothe-
TCDD (2,3,7,8-tetrachlorodibenzo-p-
sis of cancer initiation, which postulates that cancer results
dioxin), phenobarbital,
from more than a single mutation in the DNA. Statistical β-naphthoflavone, peroxisome
analysis of the data revealed that dominantly inherited pre- proliferators and polybrominated
disposition to retinoblastoma needs a germline mutation biphenyls are hepatic tumor promoters
Mirex (an organochlorine) is a promoter
(the inherited “first hit”), while tumor development
in both skin and liver
requires a second mutation, which is somatic.
Saccharin is a bladder tumor promoter
Nonhereditary retinoblastoma also requires two hits, but
Tumor Benzene
both are somatic. The two-hit hypothesis is the simplest
progression Benzoyl peroxide
form of the multiple hit hypothesis of carcinogenesis first agents(no 2,5,2 5 -tetrachlorobiphenyl
0 0
proposed by Nordling (1953) and postulating that cancer initiator activity)
results from multiple genetic mutations (hits). In the two-
hit hypothesis, the first hit required for tumor development
is part of the initiation step discussed above. DNA adduct
formation, (i.e., covalent bonding of the initiator with the Table 20.3 describes the mechanisms of action of
DNA) is an important mechanism of tumor initiation two representative tumor initiators, DMBA and MNU;
because adducts have the potential to induce mutations. Table 20.4 lists some common tumor initiators.