Mechanisms of action of quinone-containing alkylating agents: DNA alkylation by aziridinylquinones

2000 ◽  
Vol 5 (1) ◽  
pp. e172 ◽  
Author(s):  
Robert, H. J. Hargreaves
Keyword(s):  
Alkylating Agents ◽  
Mechanisms Of Action ◽  
Dna Alkylation

scholarly journals A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 453 ◽  
Author(s):  
Sudhir Raghavan ◽  
David S. Baskin ◽  
Martyn A. Sharpe
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Adducts ◽  
Alkylating Agents ◽  
Chemotherapeutic Agents ◽  
Dna Alkylation ◽  
Methylated Dna ◽  
Methylguanine Methyltransferase ◽  
Discrete Populations

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.

scholarly journals Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes

PLoS Biology ◽  
2017 ◽  
Vol 15 (11) ◽  
pp. e2002810 ◽  
Author(s):  
Thai Q. Tran ◽  
Mari B. Ishak Gabra ◽  
Xazmin H. Lowman ◽  
Ying Yang ◽  
Michael A. Reid ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Alkylating Agents ◽  
Dna Alkylation ◽  
Alkylation Damage

scholarly journals Bacterial DNA repair genes and their eukaryotic homologues: 3. AlkB dioxygenase and Ada methyltransferase in the direct repair of alkylated DNA.

2007 ◽  
Vol 54 (3) ◽  
pp. 459-468 ◽  
Author(s):  
Jadwiga Nieminuszczy ◽  
Elzbieta Grzesiuk
Keyword(s):  
Adaptive Response ◽  
Alkylating Agents ◽  
Mechanisms Of Action ◽  
Dna Bases ◽  
Mutagenic Action ◽  
Bacterial Dna ◽  
E Coli ◽  
Sublethal Doses ◽  
Ada Protein ◽  
Repair Genes

Environmental and endogenous alkylating agents generate cytotoxic and mutagenic lesions in DNA. Exposure of prokaryotic cells to sublethal doses of DNA alkylating agents induces so called adaptive response (Ada response) involving the expression of a set of genes which allows the cells to tolerate the toxic and mutagenic action of such agents. The Ada response includes the expression of four genes: ada, alkA, alkB, and aidB. The product of ada gene, Ada protein, is an activator of transcription of all four genes. DNA bases damaged by alkylation are removed by distinct strategies. The most toxic lesion 3meA is removed by specific DNA glycosylase initiating base excising repair. The toxic and mutagenic O6meG is repaired directly by methyltransferases. 1meA and 3meC are corrected by AlkB DNA dioxygenase. The mechanisms of action of E. coli AlkB dioxygenase and its human homologs ABH2 and ABH3 are described in more details.

Principles of chemotherapy

2016 ◽  
pp. 186-195
Author(s):  
David Kerr ◽  
Daniel Haller ◽  
Jaap Verweij
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Alkylating Agents ◽  
Cell Signalling ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Dose Intensity ◽  
Mechanisms Of Action ◽  
Vinca Alkaloids ◽  
Neoadjuvant Systemic Therapy

This chapter discusses the principles of chemotherapy, and includes information on the mechanism of action of commonly available drugs (anthracyclines, Vinca alkaloids, taxenes, alkylating agents, bleomycin, platinum–based agents, antimetabolites, topoisomerase inhibitors, hormonal agents, antiandrogens, cell signalling inhibitors, and growth factor receptor inhibitors), cellular principles of chemotherapy, pharmacological principles of chemotherapy (effects of hepatic and renal impairment, pharmacogenetics, dose intensity, locoregional drug administration, increase of the dose per administration, and treatment intervals), principles of combination chemotherapy (activity as a single agent, different mechanisms of action and resistance, dose-limiting toxicities, and cell-cycle-related and biochemical interactions), and adjuvant and neoadjuvant systemic therapy.

Embryotoxicity Induced by Alkylating Agents. Some Methodological Aspects of DNA Alkylation Studies in Murine Embryos Using Ethylmethanesulfonate

1987 ◽  
Vol 42 (5) ◽  
pp. 613-626 ◽  
Author(s):  
T. Platzek ◽  
G. Bochert ◽  
U. Rahm ◽  
D. Neubert
Keyword(s):  
Nuclear Dna ◽  
Alkylating Agents ◽  
Dna Alkylation ◽  
Appreciable Amount ◽  
Embryonic Tissues ◽  
Pregnant Mice ◽  
Teratogenic Potential ◽  
Methodological Aspects ◽  
Dna Purine Bases

Abstract Synthesis and spectroscopic analysis of some alkylated DNA purine bases are described. HPLC separation methods are developed for the determination of DNA alkylation rates in mammalian embryonic tissues. Following treatment of pregnant mice with the ethylating agent ethyl-methanesulfonate (EMS), an appreciable amount of alkylation (ethylation and methylation) was found in the nuclear DNA of the embryos during organogenesis. The results are discussed in context of our thesis that a certain amount of DNA alkylation in the embryos is correlated to the teratogenic potential of alkylating agents.

scholarly journals Systemic Treatments for Noninfectious Vitreous Inflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Angela Jiang ◽  
Jillian Wang ◽  
Malav Joshi ◽  
John Byron Christoforidis
Keyword(s):  
Adverse Effects ◽  
Systemic Treatment ◽  
Alkylating Agents ◽  
Calcineurin Inhibitors ◽  
Mechanisms Of Action ◽  
Biologic Agents ◽  
New Drugs ◽  
The Past ◽  
Systemic Treatments ◽  
Autoimmune Processes

Vitreous inflammation, or vitritis, may result from many causes, including both infectious and noninfectious, including rheumatologic and autoimmune processes. Vitritis is commonly vision threatening and has serious sequelae. Treatment is frequently challenging, but, today, there are multiple methods of systemic treatment for vitritis. These categories include corticosteroids, antimetabolites, alkylating agents, T-cell inhibitors/calcineurin inhibitors, and biologic agents. These treatment categories were reviewed last year, but, even over the course of just a year, many therapies have made progress, as we have learned more about their indications and efficacy. We discuss here discoveries made over the past year on both existing and new drugs, as well as reviewing mechanisms of action, clinical dosages, specific conditions that are treated, adverse effects, and usual course of treatment for each class of therapy.

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