Nitrosamine carcinogenesis

the importance of the persistence in DNA of alkylated bases in the organotropism of tumour induction

Anthony Pegg, J. W. Nicoll

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54 Citations (Scopus)

Abstract

The relationship between the incidence of tumours in various organs of the rat after the administration of dimethylnitrosamine (DMN) or diethylnitrosamine (DEN) and the formation and persistence of various alkylated nucleosides in DNA has been studied. It was found that after treatment with DMN or DEN, the initial alkylation of liver DNA was almost an order of magnitude greater than that of kidney DNA. The rate of loss of 7 alkylguanine from DNA was about the same for both tissues. Also, the amount of 7 methylguanine formed in DNA after treatment with DMN was much greater than the the amount of 7 ethylguanine produced by an approximately equicarcinogenic dose of DEN. Thus, as previously reported by others, there was no obvious correlation between the occurrence of 7 alkylguanine in DNA and the tumour producing activity of the nitrosamines. However, there was a much better correlation between the formation and persistence of 06 alkylguanines and tumour incidence. Although the overall level of alkylation (as measured by the amount of the major product formed which in all cases was 7 alkylguanine) was an order of magnitude greater with DMN than with DEN, relatively more of the 06 guanine derivative was formed after treatment with the ethylating agent. Thus the ratio of alkylation of guanine at the 06 position compared to the N7 position was 0.1 for DMN and 0.5 for DEN. Moreover, after a large dose of DMN, which produces kidney tumours but not liver tumours, 06 methylguanine was much longer lived in the kidney DNA than in the liver. There was much less difference between the relative stability of this product in the DNA from the liver and the kidney of rats treated with a low dose of DMN (repeated administration of such doses does give rise to liver cancer). These experiments support the hypothesis that the formation and persistence until cell division of certain promutagenic products such as 06 alkylguanine might be responsible for the initiation of tumours and that the differing abilities of cells in various organs to catalyze the repair of such products might account for part of the differing susceptibilities of tissues to the carcinogenic stimulus provided by the nitrosamines. Preliminary experiments have confirmed that liver extracts are capable of removing 06 alkylguanine from DNA in vitro and the properties of this system are being studied.

Original languageEnglish (US)
Pages (from-to)571-592
Number of pages22
JournalIARC (International Agency for Research on Cancer) Scientific Publications
Volumeno.12
StatePublished - Jan 1 1976

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Nitrosamines
Dimethylnitrosamine
Carcinogenesis
Diethylnitrosamine
DNA
Neoplasms
Alkylation
Kidney
Liver
Guanine
Liver Extracts
Incidence
Liver Neoplasms
Nucleosides
Cell Division

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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title = "Nitrosamine carcinogenesis: the importance of the persistence in DNA of alkylated bases in the organotropism of tumour induction",
abstract = "The relationship between the incidence of tumours in various organs of the rat after the administration of dimethylnitrosamine (DMN) or diethylnitrosamine (DEN) and the formation and persistence of various alkylated nucleosides in DNA has been studied. It was found that after treatment with DMN or DEN, the initial alkylation of liver DNA was almost an order of magnitude greater than that of kidney DNA. The rate of loss of 7 alkylguanine from DNA was about the same for both tissues. Also, the amount of 7 methylguanine formed in DNA after treatment with DMN was much greater than the the amount of 7 ethylguanine produced by an approximately equicarcinogenic dose of DEN. Thus, as previously reported by others, there was no obvious correlation between the occurrence of 7 alkylguanine in DNA and the tumour producing activity of the nitrosamines. However, there was a much better correlation between the formation and persistence of 06 alkylguanines and tumour incidence. Although the overall level of alkylation (as measured by the amount of the major product formed which in all cases was 7 alkylguanine) was an order of magnitude greater with DMN than with DEN, relatively more of the 06 guanine derivative was formed after treatment with the ethylating agent. Thus the ratio of alkylation of guanine at the 06 position compared to the N7 position was 0.1 for DMN and 0.5 for DEN. Moreover, after a large dose of DMN, which produces kidney tumours but not liver tumours, 06 methylguanine was much longer lived in the kidney DNA than in the liver. There was much less difference between the relative stability of this product in the DNA from the liver and the kidney of rats treated with a low dose of DMN (repeated administration of such doses does give rise to liver cancer). These experiments support the hypothesis that the formation and persistence until cell division of certain promutagenic products such as 06 alkylguanine might be responsible for the initiation of tumours and that the differing abilities of cells in various organs to catalyze the repair of such products might account for part of the differing susceptibilities of tissues to the carcinogenic stimulus provided by the nitrosamines. Preliminary experiments have confirmed that liver extracts are capable of removing 06 alkylguanine from DNA in vitro and the properties of this system are being studied.",
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N2 - The relationship between the incidence of tumours in various organs of the rat after the administration of dimethylnitrosamine (DMN) or diethylnitrosamine (DEN) and the formation and persistence of various alkylated nucleosides in DNA has been studied. It was found that after treatment with DMN or DEN, the initial alkylation of liver DNA was almost an order of magnitude greater than that of kidney DNA. The rate of loss of 7 alkylguanine from DNA was about the same for both tissues. Also, the amount of 7 methylguanine formed in DNA after treatment with DMN was much greater than the the amount of 7 ethylguanine produced by an approximately equicarcinogenic dose of DEN. Thus, as previously reported by others, there was no obvious correlation between the occurrence of 7 alkylguanine in DNA and the tumour producing activity of the nitrosamines. However, there was a much better correlation between the formation and persistence of 06 alkylguanines and tumour incidence. Although the overall level of alkylation (as measured by the amount of the major product formed which in all cases was 7 alkylguanine) was an order of magnitude greater with DMN than with DEN, relatively more of the 06 guanine derivative was formed after treatment with the ethylating agent. Thus the ratio of alkylation of guanine at the 06 position compared to the N7 position was 0.1 for DMN and 0.5 for DEN. Moreover, after a large dose of DMN, which produces kidney tumours but not liver tumours, 06 methylguanine was much longer lived in the kidney DNA than in the liver. There was much less difference between the relative stability of this product in the DNA from the liver and the kidney of rats treated with a low dose of DMN (repeated administration of such doses does give rise to liver cancer). These experiments support the hypothesis that the formation and persistence until cell division of certain promutagenic products such as 06 alkylguanine might be responsible for the initiation of tumours and that the differing abilities of cells in various organs to catalyze the repair of such products might account for part of the differing susceptibilities of tissues to the carcinogenic stimulus provided by the nitrosamines. Preliminary experiments have confirmed that liver extracts are capable of removing 06 alkylguanine from DNA in vitro and the properties of this system are being studied.

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