Biomaterial Database

Alkylating agents and DNA polymerases. 2006

Leon P Bignold

Institute of Medical and Veterinary Science, Adelaide, SA 5001, Australia. leon.bignold@adelaide.edu.au

Alkylating agents, for example nitrogen "mustards", are variably toxic, mutagenic, carcinogenic and teratogenic, but by mechanisms which have not been clearly established. In particular, the mechanisms both of their delayed toxic effects (which are primarily against dividing cells, in association with retardation of the rate of cell division, disruption of mitoses, and breakages and other abnormalities of chromosomes) and of their carcinogenic actions are not understood. The literature on the testing of thousands of analogues has demonstrated great variability of effects on the various cell biological phenomena, and no aspect of chemical structure or biochemical reactivity of these agents has been established as especially related to any particular effect. Here theories of the mechanisms of action of alkylating agents are reviewed and it is suggested that impairment of the functions of DNA polymerase complexes might contribute to some of the effects of alkylating agents. In particular, impairment of replicative fidelity of DNA during the S-phase could contribute to some of the mitotic and chromosomal effects, as well as to their carcinogenic and teratogenic potencies. Some aspects of testing the effects of alkylating agents on components of the DNA synthetic pathway are mentioned. Emphasis is given to consideration of the various relevant levels (conventional plasma/tissue; tissue/tumour cell cytoplasm; tumour cell cytoplasm/tumour cell nucleus and tumour nuclear karyoplasm/tumour chromatin] of the pharmacokinetics and pharmacodynamics of the agents and their metabolites.

UI	MeSH Term	Description	Entries
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D009151	Mustard Gas	Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed).	Dichlorodiethyl Sulfide,Sulfur Mustard,Bis(beta-chloroethyl) Sulfide,Di-2-chloroethyl Sulfide,Mustardgas,Psoriazin,Yellow Cross Liquid,Yperite,Di 2 chloroethyl Sulfide,Gas, Mustard,Mustard, Sulfur,Sulfide, Di-2-chloroethyl,Sulfide, Dichlorodiethyl
D004259	DNA-Directed DNA Polymerase	DNA-dependent DNA polymerases found in bacteria, animal and plant cells. During the replication process, these enzymes catalyze the addition of deoxyribonucleotide residues to the end of a DNA strand in the presence of DNA as template-primer. They also possess exonuclease activity and therefore function in DNA repair.	DNA Polymerase,DNA Polymerases,DNA-Dependent DNA Polymerases,DNA Polymerase N3,DNA Dependent DNA Polymerases,DNA Directed DNA Polymerase,DNA Polymerase, DNA-Directed,DNA Polymerases, DNA-Dependent,Polymerase N3, DNA,Polymerase, DNA,Polymerase, DNA-Directed DNA,Polymerases, DNA,Polymerases, DNA-Dependent DNA
D004261	DNA Replication	The process by which a DNA molecule is duplicated.	Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000477	Alkylating Agents	Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.	Alkylating Agent,Alkylator,Alkylators,Agent, Alkylating,Agents, Alkylating
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D018906	Antineoplastic Agents, Alkylating	A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)	Alkylating Agents, Antineoplastic,Alkylating Antineoplastic Agents,Alkylating Antineoplastic Drugs,Alkylating Antineoplastics,Alkylating Drugs, Antineoplastic,Antineoplastic Alkylating Agents,Antineoplastic Drugs, Alkylating,Antineoplastics, Alkylating,Antineoplastic Alkylating Drugs,Drugs, Antineoplastic Alkylating
D019384	Nucleic Acid Synthesis Inhibitors	Compounds that inhibit cell production of DNA or RNA.	DNA Polymerase Inhibitor,DNA Synthesis Inhibitor,DNA Synthesis Inhibitors,Nucleic Acid Synthesis Inhibitor,RNA Synthesis Inhibitor,RNA Synthesis Inhibitors,DNA Polymerase Inhibitors,Inhibitors, DNA Synthesis,Inhibitors, Nucleic Acid Synthesis,Inhibitors, RNA Synthesis,Inhibitor, DNA Polymerase,Inhibitor, DNA Synthesis,Inhibitor, RNA Synthesis,Inhibitors, DNA Polymerase,Polymerase Inhibitor, DNA,Polymerase Inhibitors, DNA,Synthesis Inhibitor, DNA,Synthesis Inhibitor, RNA,Synthesis Inhibitors, DNA,Synthesis Inhibitors, RNA