Tumor initiation

Cavalier E, E Rogan (1998) Mechanisms of tumor initiation by polycyclic aromatic hydrocarbons in mammals. Handbook Environ Chem 3J 82-117. 

Zahid, M. Kohli, E. Saeed, M. Rogan, E. Cavalieri, E. The greater reactivity of estradiol-3,4-quinone vs. estradiol-2,3-quinone with DNA in the formation of depurinating adducts implications for tumor-initiating activity. Chem. Res. Toxicol. 2006, 19, 164-172. 

It is assumed that there is no absolute threshold for carcinogenic response, although detoxification nechanisms may prevent tumor initiation at low doses. 

Dose-Response Extrapolation Models. A dose-response model is simply a hypothetical mathematical relationship between dose-rate and probability of response. For example, the simplest form of such a model asserts that probability of tumor initiation is a linear multiple of dose-rate (provided the dosage is well below the organism s acute effect threshold for the substance in question). In general, we will express dose-response models as follows ... 

The "one-hit" hypothesis states that the tumor initiation is a Poisson process, in that each additional molecule of a carcinogen produces an equal increment in the probability of a response, and that all such "hits" are independent. Consequently,... 

Tumor Initiation in Mouse Skin Metabolite Activity/Activity of BP at Same Dose... 

Tumor Initiation in Mouse Skin Metabolite Activity/Activity of BP at Same Dose Lung Adenoma Induction in Newborn Mice Metabolite Activity/Activity of BP at Same Dose ... 

Although benz(a)anthracene (BA) is generally considered noncarcino-genic (27), it is a weak tumor initiator when administered with a phorbol ester promoter (28). More importantly, BA is a convenient model for the highly potent carcinogenic PAH 7,12-dimethylbenz(a)-anthracene and 3-methylcholanthrene (27), both of which are BA derivatives but which offer more serious synthetic problems. 

Chrysene is a weak tumor initiator and is inactive as a complete carcinogen (38). The 1,2-dihydrodiol is more active as a mutagen than the 3,4- or the 5,6-dihydrodiols. The biological data support the hypothesis that the principal active metabolite of chrysene is the bay region anti-1,2-diol-3,4-epoxide (58). 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

Fluoranthene is one of the more prevalent PAH in the human environment. Although fluoranthene is not active as a carcinogen, its 2- and 3-methyl derivatives have been shown to be active as tumor initiators (105). The major mutagenic metabolite of fluoranthene in the Ames assay has been identified as the 2,3-dihydrodiol (31)... 

Benzo(b)-, benzo(k)-, and benzo(j)fluoranthene are common environmental contaminants (38). The tumor-initiating activity of benzo-(b)fluoranthene on mouse skin is about equal to that of DBA (38). All three isomers are mutagenic in the Ames assay (110). Syntheses of the 1,2-, 9,10-, and 11,12-dihydrodiols of benzo(b)fluoranthene by Method I have been reported (111,112). 

Methylphenanthrene fulfills the structural requirements but, as in the case of the other monomethylphenanthracenes, is inactive as a tumor initiator on mouse skin ( 5). This seems to be due to facile metabolic detoxification by formation of the 9,10-dihydrodiol, a process which is blocked in the tumorigenic isomers 1,4- and 4,10-dime thy lphenanthrene ( 5,j>). Among the methylated benzoicIphenan-threnes, the 3-,4-,5-, and 6-methyl isomers are the most tumori-genic The 1-methyl isomer, in which the methyl group is present in a 4-sided "fjord , is only weakly active like the parent hydrocarbon (23). 

Table II. Tumor Initiating Activity of 5-MeC Metabolites on Mouse Skin...

PAH radical cations are also involved in the metabolic conversion of PAH to PAH diones. Carcinogenicity studies of PAH in rat mammary gland indicate that only PAH with ionization potential low enough for activation by one-electron oxidation induce tumors in this target organ. These results and others indicate that one-electron oxidation of PAH is involved in their tumor initiation process. 

Covalent binding of chemical carcinogens to cellular macromolecules, DNA, RNA and protein, is wel1-accepted to be the first step in the tumor initiation process ( 1, 2). Most carcinogens, including polycyclic aromatic hydrocarbons (PAH), require metabolic activation to produce the ultimate electrophilic species which react with cellular macromolecules. Understanding the mechanisms of activation and the enzymes which catalyze them is critical to elucidating the tumor initiation process. 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

Cavalieri, E., R. Roth, E. Rogan C. Grandjean, and J. Althoff. 1978. Mechanisms of tumor initiation by polycyclic aromatic hydrocarbons. Pages 273-284 in P.W. Jones and R.I. Freudenthal (eds.). Carcinogenesis — A Comprehensive Survey. Vol. 3. Polynuclear Aromatic Hydrocarbons Second International Symposium on Analysts, Chemistry, and Biology. Raven Press, New York. 

DiGiovanni, J. and T.J. Slaga. 1981a. Effects of benzo(e)pyrene [B(e)P] and dibenz(a,c)anthracene [DB(a,c)A] on the skin tumor-initiating activity of polycyclic aromatic hydrocarbons. Pages 17-31 in M. Cooke and A.J. Dennis (eds.). Chemical Analysis and Biological Fate Polynuclear Aromatic Hydrocarbons. Fifth International Symposium. Battelle Press, Columbus, OH. 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

Phenol has been tested in animals for carcinogenicity by the oral and dermal routes, but results are equivocal. In a chronic NCI cancer bioassay (NCI 1980), a significant incidence of tumors (pheochro-mocytomas of the adrenal gland, leukemia, or lymphomas) occurred only in male rats exposed to the lowest dose level (2,500 ppm, 277 mg/kg/day) of phenol but not in male or female mice or male rats exposed to a higher dose level (5,000 ppm, 624 mg/kg/day). Since tumors occurred only in males in one of the two species tested, and since a positive dose-response relationship was not established, this study does not provide sufficient evidence to conclude that phenol is carcinogenic when administered by the oral route. Dermal application of phenol has been shown to result in tumors in mice phenol is a tumor promoter when it is applied after the application of the tumor initiator DMBA (Boutwell and Bosch 1959 Salaman and Glendenning 1957 Wynder and Hoffmann 1961). However, this effect occurs at dose levels of phenol that produce severe skin... 

Phenol is a tumor promoter in laboratory animals. In mice, dermal exposure to phenol in benzene (Boutwell and Bosch 1959) or in acetone (Salaman and Glendenning 1957 Wynder and Hoffmann 1961) increased the incidence of tumors resulting from dermal exposure to the tumor initiator, DMBA. When injected with mixtures of phenol and hydroquinone, a hydrolyzed metabolite of phenol, mice exhibited significantly depressed bone marrow erythropoiesis compared to injection with phenol alone (Chen and Eastmond 1995a). The involvement of peripheral acetylcholine in phenol-induced tremors was implicated by studies in which mice were injected with phenol and pentobarbital, an inhibitor of acetylcholine release (Itoh 1995). 

In mice, also, deacetylation is involved in the hepato-carcinogenesis induced by 2-(acetylamino)fluorene. Indeed, BNPP-inhibited DNA-adduct formation in murine liver microsomes as well as tumor initiation by A-hydroxy-2-(acetylamino)fluorene in infant male B6C3Fj mice [100],... 

Calkins WH, Deye JF, Hartgrove RW, et al. 1981. Synthetic crude oils from coal Mutagenicity and tumor-initiation screening tests. Department of Energy Symposium Series 54 462-470. 

Gerhart JM, Hatoum NS, Haider CA, et al. 1988. Tumor initiation and promotion effects of petroleum... 

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