Alkylating Agents as Environmental Carcinogen and Chemotherapy Agents

Yildiz Dincer, PhD (Editor)
Istanbul University- Cerrahpasa, Cerrahpasa Medical Faculty, Department of Medical Biochemistry, Istanbul, Turkey

Series: Cell Biology Research Progress, Cancer Etiology, Diagnosis and Treatments
BISAC: MED009000

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Volume 10

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Special issue: Resilience in breaking the cycle of children’s environmental health disparities
Edited by I Leslie Rubin, Robert J Geller, Abby Mutic, Benjamin A Gitterman, Nathan Mutic, Wayne Garfinkel, Claire D Coles, Kurt Martinuzzi, and Joav Merrick

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Alkylating agents are an important class of carcinogens. O6-methylguanine (O6 MG) formed in cellular DNA by alkylating agents is a mutagenic lesion. Reactive metabolites, which are capable of alkylate in the DNA base, are produced during the catabolism of precursors of alkylating agents in the diet. Active alkylating agents can also be synthesized endogenously in the body. Endogenous alkylating agents are produced via nitrosation of primary amines by nitrates and nitrous anhydride formed by nitric oxide. Exposure of alkylating agents is at a minimum level in daily life. However, vegetables, drinking water, beer, tobacco, various drugs, processed cheese, meat and fish products contain a considerable amount of alkylating agents.

Smoked and salted meat-fish consumption is found to be related with an increased risk of mouth, pharynx, esophagus, colon and gastric cancers. It is suggested that childhood leukemia and brain tumors are related to sausage consumption by their parents. In recent investigations, increased production of endogenous nitrates and nitrosamines in chronic infectious and inflammatory conditions has been suggested as a contributory factor for increased cancer risk. O6-MG adducts are repaired by the DNA repair protein, O6-methylguanine DNA methyltransferase (O6-MGMT). This nuclear enzyme repairs O6-MG adducts by transferring the methyl group to itself at a specific cysteine residue. As a result of this, automethylation O6-MGMT become inactivated and are not regenerated. Cells with low O6-MGMT level are more susceptible to cytotoxic and mutagenic effects of alkylating agents. On the other hand, alkylating agents are used in certain chemotherapy regimens. Various investigators determined that O6-MGMT is at a high level in human tumors, thus they exhibit resistance to chemotherapy, including alkylating agents. Various anaolgs of O6-MG were suggested as a potential adjuvant in combination chemotherapy with alkylating agents to treat O6-MGMT proficient tumors.

The susceptibility of any tissue to mutagenic effect of alkylating agents is dependent upon the balance between the ability of the tissue to metabolise alkylating agents to carcinogenic intermediates, the extent of O6-MG formation, rate of repair by O6-MGMT and the extent of DNA replication which occurs when O6-MG is present. This book is a reliable reference for the sources of alkylating agents and their effects in human body. (Imprint: Nova Biomedical )

Preface pp. i-viii

Chapter 1. Carcýnogenesýs
(Yildiz Dincer, Istanbul University Cerrahpasa Medical Faculty, Department of Biochemistry, Istanbul, Turkey)pp. 1-26

Chapter 2. Alkylatýng Agent Exposure and its Relatýon wýth Cancer Rýsk
(Yildiz Dincer, Istanbul University Cerrahpasa Medical Faculty, Department of Biochemistry, Istanbul, Turkey)pp. 27-68

Chapter 3. Alkylatýng Agents in Chemotherapy
(Tiraje Celkan, Istanbul University Cerrahpasa Medical Faculty, Department of Pediatric Hematology, Istanbul, Turkey)pp. 69-100
Chapter 4. Resýstance Mechanýsms for Alkylatýng Agent-Medýated Chemotherapy
(Ilhan Onaran, Istanbul University Cerrahpasa Medical Faculty, Department of Medical Biology, Istanbul, Turkey)pp. 101-144

Chapter 5. Alkylatýng Agents and Treatment of Glýomas
(Tsuyoshi Fukushima, Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan)pp. 145-170
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Index pp. 171-186

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