Oxidation of DNA bases by tumor promoter-activated processes.

Abstract

Evidence has accumulated showing that active oxygen species participate in at least one stage of tumor promotion. Tumor promoters can induce various types of cells to undergo processes that result in formation of active oxygen species. They stimulate polymorphonuclear leukocytes (PMNs) to undergo an oxidative burst that is characterized by rapid formation of * 0 -and H202. We find that in vitro formation of H202 by tumor promoter-activated PMNs correlates with their in vivo first-stage promoting activity. Moreover, two thymidine derivatives are formed in DNA coincubated with tumor promoter-stimulated PMNs: 5-hydroxymethyl-2 '-deoxyuridine (HMdU) and thymidine glycol (dTG). The amounts of HMdU and dGl formed correlate with the first-stage tumor-promoting potencies of the agents used for PMN stimulation and with the amount of H202 generated. We find that HMdU is also formed in the DNA of HeLa cells coincubated with 12-0-tetradecanoylphorbol-13-acetate (TPA)-activated PMNs, with the amount of HMdU being proportional to that of TPA used. Even in the absence of PMNs, HMdU is increasingly formed in cellular DNA with increased TPA concentration, although at much lower levels than in the presence of PMN&s When rat liver microsomes are incubated with benzo[a]pyrene (BaP), a complete carcinogen, H202 is also generated. Production of H202 increases linearly with increasing concentrations of BaP. Furthermore, HMdU is formed in DNA exposed to BaP-treated microsomes, and its formation is ithibited by catalase. These results suggest that carcinogen-induced processes generating H202 are associated with the first-stage promoting activity of complete carcinogens.

Use of Moracin in preventing the cancer

“…The present attempt, further illustrates the suppression in the proliferationrelated genes, c-fos and c-myc, by topical application of Moracin. The cfos and c-myc have been associated with a variety of carcinogenesis ( 17 ).The attempts on in vitro have shown that, ROS stimulate the generation of protooncogenes c-fos, c-myc and others in various cell system ( 18 and 19), and that TPA could stimulate the generation of such active oxygen species in vivo ( 20 ). Expression of cfos was found elevated in DMBA / TPAinduced mouse skin ( 16 and 21), which revealed that, topical application of Moracin significantly reduced the expression of epidermal c-fos and c-myc and that labeling index of 4 -HNE was correlated with those of c-fos and c-myc.…”

Perspectives on the risk assessment for nongenotoxic carcinogens and tumor promoters.

“…This has led individual researchers to define these criteria arbitrarily. Thus, at one end of the spectrum the term has been narrowly defined as "positive in the Ames assay" while at the other extreme is the broadest definition, which includes the ability, directly or indirectly, to damage or alter the genetic material (17,25,26). In between are permutations shown in Table 2, which well illustrate the arbitrary nature of the exercise.…”

“…During the past several years, evidence has developed that some type ofheritable imprinting is also involved in tumor promotion, possibly via an indirect genetic mechanism (14,25,33,(35)(36)(37)(38)(39). Recent studies indicate that tumor promoters can induce genomic changes-albeit indirectly-through induction of free radicals and superoxides that react with DNA and cause molecular lesions (such as thymine glycol and other altered nucleic acid structures) (4,17,26,33,41,42). Thus, indirect genotoxicity has been implicated in the induction of chromosomal aberrations by TPA (25) and in the formation of DNA strand breaks in human leukocytes by benzoyl peroxide, another potent tumor promoter (43).…”

DNA damage, environmental toxicants, and rate of aging

“…For example, although benzo(a)pyrene (BaP) 46 is not a direct generator of free radicals, recent investigations implicate oxidative processes in its carcinogenic effect. 47 …”

“…BaP diol epoxide-DNA adducts are responsible for its initiation properties. 47 These adducts are easily detectable in lymphocytes of individuals exposed to high levels of BaP, such as foundry and cokeoven workers. The mechanisms of the tumor-promoting activities of BaP, however, are not clear.…”