Published in Cancer Detection and Prevention 1997; 21(5):391-405.

Dna Adducts and the Mechanism of Carcinogenesis and Cytotoxicity of Methylating Agents of Environmental and Clinical Significance

Soterios A Kyrtopoulosa, Lucy M Andersonb, Saranjit K Chhabrab, Vassilis L SouliotiSa, Vassiliki Pletsaa, Christos Valavanisa, Panagiotis Georgiadisa

aNational Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece; bLaboratory of Comparative Carcinogenesis, National Cancer Institute, Frederic Cancer Research and Development Center, Ft. Frederick, MD

ABSTRACT: DNA adducts are covalent complexes formed between genotoxic carcinogens and DNA bases, and constitute a critical early intermediate step on the pathway of chemical carcinogenesis. Their accumulation in different tissues reflects the amount of activated carcinogen reaching DNA, and can therefore serve as an index of the biologically relevant dose reaching the target tissues or cells. DNA adducts induced by methylating agents are of interest in view of their occurrence in the environment and their use as cytotoxic drugs in cancer chemotherapy. Current evidence indicates that 06-methylguanine plays a particularly important role in the mutagenic, carcinogenic, and cytotoxic activities of methylating agents. O6-ethylguanine is repaired efficiently by the enzyme 06-alkylguanine-DNA alkyltransferase (AGT). Lack of this enzyme results in excessive accumulation of 06-methylguanine and recent evidence suggests that significant quantitative effects on adduct accumulation may be linked to conditions of very low AGT levels. This would be important from the point of view of clinical practice, since modulation of AGT is under investigation as a means of enhancing the therapeutic efficacy of clinical agents acting via the production of O6-methylguanine and related adducts, such as, for example, procarbazine, dacarbazine, and some nitrosoureas. The measurement of O6-methylguanine has been employed as a marker to investigate the role of environmental methylating agents in human carcinogenesis. While the nature and origin of the methylating agents responsible for these adducts is currently unknown, recent studies in patas monkeys have shown that N-nitrosodimethylamine, a methylating carcinogen to which human exposure is well documented, is capable of efficiently generating O6-methylguanine in most tissues, including fetal tissues. Furthermore, it has been found that this damage is substantially enhanced by the coadministration of ethyl alcohol which acts by inhibiting the liver first-pass metabolism of the carcinogen, an observation which supports the hypothesis that alcohol consumption may act as a risk factor in human carcinogenesis by augmenting the action of nitrosamines.

KEY WORDS: methylating agents, methylating cytostatic drugs, molecular epidemiology, Nnitrosodimethylamine, O^6-methylguanine, transplacental carcinogenesis.

For more information, contact