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