Biomaterial Database

Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. 1998

Y Pommier, and P Pourquier, and Y Fan, and D Strumberg

Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892-4255, USA. pommier@nih.gov

DNA topoisomerase I is essential for cellular metabolism and survival. It is also the target of a novel class of anticancer drugs active against previously refractory solid tumors, the camptothecins. The present review describes the topoisomerase I catalytic mechanisms with particular emphasis on the cleavage complex that represents the enzyme's catalytic intermediate and the site of action for camptothecins. Roles of topoisomerase I in DNA replication, transcription and recombination are also reviewed. Because of the importance of topoisomerase I as a chemotherapeutic target, we review the mechanisms of action of camptothecins and the other topoisomerase I inhibitors identified to date.

UI	MeSH Term	Description	Entries
D007364	Intercalating Agents	Agents that are capable of inserting themselves between the successive bases in DNA, thus kinking, uncoiling or otherwise deforming it and therefore preventing its proper functioning. They are used in the study of DNA.	Intercalating Agent,Intercalating Ligand,Intercalative Compound,Intercalator,Intercalators,Intercalating Ligands,Intercalative Compounds,Agent, Intercalating,Agents, Intercalating,Compound, Intercalative,Compounds, Intercalative,Ligand, Intercalating,Ligands, Intercalating
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
D011083	Polycyclic Compounds	Compounds which contain two or more rings in their structure.	Compounds, Polycyclic
D002166	Camptothecin	An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA TOPOISOMERASES, TYPE I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity.	Camptothecine
D004247	DNA	A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).	DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004264	DNA Topoisomerases, Type I	DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.	DNA Nicking-Closing Protein,DNA Relaxing Enzyme,DNA Relaxing Protein,DNA Topoisomerase,DNA Topoisomerase I,DNA Topoisomerase III,DNA Topoisomerase III alpha,DNA Topoisomerase III beta,DNA Untwisting Enzyme,DNA Untwisting Protein,TOP3 Topoisomerase,TOP3alpha,TOPO IIIalpha,Topo III,Topoisomerase III,Topoisomerase III beta,Topoisomerase IIIalpha,Topoisomerase IIIbeta,DNA Nicking-Closing Proteins,DNA Relaxing Enzymes,DNA Type 1 Topoisomerase,DNA Untwisting Enzymes,DNA Untwisting Proteins,Topoisomerase I,Type I DNA Topoisomerase,III beta, Topoisomerase,III, DNA Topoisomerase,III, Topo,III, Topoisomerase,IIIalpha, TOPO,IIIalpha, Topoisomerase,IIIbeta, Topoisomerase,Topoisomerase III, DNA,Topoisomerase, TOP3,beta, Topoisomerase III
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000970	Antineoplastic Agents	Substances that inhibit or prevent the proliferation of NEOPLASMS.	Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D015394	Molecular Structure	The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.	Structure, Molecular,Molecular Structures,Structures, Molecular