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Medicinal Research Reviews Mar 2012Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes... (Review)
Review
Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently, the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. This review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, chemical synthesis of PBDs, mechanism of DNA alkylation, and DNA-binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.
Topics: Actinobacteria; Aminoglycosides; Anthramycin; Antineoplastic Agents, Alkylating; Benzodiazepines; DNA; Models, Molecular; Multigene Family; Pyrroles; Structure-Activity Relationship
PubMed: 20544978
DOI: 10.1002/med.20212 -
Chemical Research in Toxicology Sep 2020The cellular outcomes of chemical exposure are as much about the cellular to the chemical as it is an of the chemical. We are growing in our understanding of the... (Review)
Review
The cellular outcomes of chemical exposure are as much about the cellular to the chemical as it is an of the chemical. We are growing in our understanding of the genotoxic interaction between chemistry and biology. For example, recent data has revealed the biological basis for mutation induction curves for a methylating chemical, which has been shown to be dependent on the repair capacity of the cells. However, this is just one end point in the toxicity pathway from chemical exposure to cell death. Much remains to be known in order for us to predict how cells will respond to a certain dose. Methylating agents, a subset of alkylating agents, are of particular interest, because of the variety of adverse genetic end points that can result, not only at increasing doses, but also over time. For instance, methylating agents are mutagenic, their potency, for this end point, is determined by the cellular repair capacity of an enzyme called methylguanine DNA-methyltransferase (MGMT) and its ability to repair the induceed methyl adducts. However, methyl adducts can become clastogenic. Erroneous biological processing will convert mutagenic adducts to clastogenic events in the form of double strand breaks (DSBs). How the cell responds to DSBs is via a cascade of protein kinases, which is called the DNA damage response (DDR), which will determine if the damage is repaired effectively, via homologous recombination, or with errors, via nonhomologous end joining, or whether the cell dies via apoptosis or enters senescence. The fate of cells may be determined by the extent of damage and the resulting strength of DDR signaling. Therefore, thresholds of damage may exist that determine cell fate. Such thresholds would be dependent on each of the repair and response mechanisms that these methyl adducts stimulate. The molecular mechanism of how methyl adducts kill cells is still to be fully resolved. If we are able to quantify each of these thresholds of damage for a given cell, then we can ascertain, of the many adducts that are induced, what proportion of them are mutagenic, what proportion are clastogenic, and how many of these clastogenic events are toxic. This review examines the possibility of dose and damage thresholds for methylating agents, from the perspective of the underlying evolutionary mechanisms that may be accountable.
Topics: Alkylating Agents; Animals; Enzyme Inhibitors; Humans; Methylation; O(6)-Methylguanine-DNA Methyltransferase
PubMed: 32388971
DOI: 10.1021/acs.chemrestox.0c00052 -
Anticancer Research 2006Alkylating agents, for example nitrogen "mustards", are variably toxic, mutagenic, carcinogenic and teratogenic, but by mechanisms which have not been clearly... (Review)
Review
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.
Topics: Alkylating Agents; Animals; Antineoplastic Agents, Alkylating; DNA Replication; DNA-Directed DNA Polymerase; Humans; Models, Molecular; Mustard Gas; Nucleic Acid Synthesis Inhibitors
PubMed: 16619541
DOI: No ID Found -
Analytical Chemistry Jan 2018
Review
Topics: Alkylating Agents; Amines; Animals; Chemistry Techniques, Analytical; DNA; DNA Adducts; DNA Damage; Heterocyclic Compounds; Humans; Reactive Oxygen Species
PubMed: 29084424
DOI: 10.1021/acs.analchem.7b04247 -
Nature Reviews. Cancer Jan 2012Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral... (Review)
Review
Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.
Topics: Alkylating Agents; Base Pair Mismatch; DNA Damage; DNA Repair; Humans
PubMed: 22237395
DOI: 10.1038/nrc3185 -
Bulletin Du Cancer Nov 2011With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even... (Review)
Review
With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.
Topics: Antineoplastic Agents, Alkylating; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; DNA, Neoplasm; Drug Synergism; Humans; Neoplasms; Poly Adenosine Diphosphate Ribose; Proteins; Tumor Suppressor Proteins
PubMed: 22020797
DOI: 10.1684/bdc.2011.1471 -
Experimental Eye Research Nov 2020This review details the current understanding of the mechanism of action and corneal effects of mitomycin C (MMC) for prophylactic prevention of stromal fibrosis after... (Review)
Review
This review details the current understanding of the mechanism of action and corneal effects of mitomycin C (MMC) for prophylactic prevention of stromal fibrosis after photorefractive keratectomy (PRK), and includes discussion of available information on dosage and exposure time recommended for MMC during PRK. MMC is an alkylating agent, with DNA-crosslinking activity, that inhibits DNA replication and cellular proliferation. It acts as a pro-drug and requires reduction in the tissue to be converted to an active agent capable of DNA alkylation. Although MMC augments the early keratocyte apoptosis wave in the anterior corneal stroma, its most important effect responsible for inhibition of fibrosis in surface ablation procedures such as PRK is via the inhibition of mitosis of myofibroblast precursor cells during the first few weeks after PRK. MMC use is especially useful when treating eyes with higher levels of myopia (≥approximately 6 D), which have shown higher risk of developing fibrosis (also clinically termed late haze). Studies have supported the use of MMC at a concentration of 0.02%, rather than lower doses (such as 0.01% or 0.002%), for optimal reduction of fibrosis after PRK. Exposure times for 0.02% MMC longer than 40 s may be beneficial for moderate to high myopia (≥6D), but shorter exposures times appear to be equally effective for lower levels of myopia. Although MMC treatment may also be beneficial in preventing fibrosis after PRK treatments for hyperopia and astigmatism, more studies are needed. Thus, despite the clinical use of MMC after PRK for nearly twenty years-with limited evidence of harmful effects in the cornea-many decades of experience will be needed to exclude late long-term effects that could be noted after MMC treatment.
Topics: Alkylating Agents; Corneal Opacity; Corneal Stroma; Fibrosis; Humans; Lasers, Excimer; Mitomycin; Myopia; Photorefractive Keratectomy; Postoperative Complications; Visual Acuity
PubMed: 32905844
DOI: 10.1016/j.exer.2020.108218 -
Journal of Neurochemistry Mar 2018Glioblastoma is a malignant brain tumor that inevitably develops resistance to standard of care drug temozolomide (TMZ) due to a population of cells called cancer stem...
Outlining involvement of stem cell program in regulation of O6-methylguanine DNA methyltransferase and development of temozolomide resistance in glioblastoma: An Editorial Highlight for 'Transcriptional control of O -methylguanine DNA methyltransferase expression and temozolomide resistance in...
Glioblastoma is a malignant brain tumor that inevitably develops resistance to standard of care drug temozolomide (TMZ) due to a population of cells called cancer stem cells (CSCs). These cells utilize progenitor cell signaling programs and develop robust DNA repair machinery. In this editorial highlight we focus on stem cell regulation of TMZ resistance and discuss findings of Happold et al. () that outline direct transcriptional regulation of DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) in glioblastoma CSCs through NFkB activation. The authors found that cells cultured in CSC propagating conditions exhibit increase in MGMT expression when compared to adherent differentiated monolayer cells. This in turn increases resistance to standard of care drug temozolomide (TMZ) in these cells. NFkB activation was found to directly activate expression of MGMT in sphere cultured GBM CSC.
Topics: Antineoplastic Agents, Alkylating; DNA; Dacarbazine; Drug Resistance, Neoplasm; Glioblastoma; Guanine; Humans; Temozolomide
PubMed: 29644711
DOI: 10.1111/jnc.14280 -
Cancer Biology & Therapy 2019Glioblastoma is the most invasive form of brain tumor. Although temozolomide chemotherapy has been shown to significantly improve survival in patients with GBM, this... (Review)
Review
Glioblastoma is the most invasive form of brain tumor. Although temozolomide chemotherapy has been shown to significantly improve survival in patients with GBM, this increase is only trivial. The underlying cause is that many GBMs do not respond to temozolomide, and the rest produces resistance. In the past two decades, many attempts have been made to understand resistance mechanisms and to combine other treatments with temozolomide to maximize patient benefit. Unfortunately, it seems to be a red queen game, and the speed of disease development is as fast as the progress in the field. In order to win this game, a comprehensive approach is needed to decipher the details of the resistance mechanism and to transfer the basic research to the clinic. This article reviews the following: temozolomide discovery, chemistry, and mechanism of action, and mechanisms of resistance, as well as combination therapy with other strategies.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; DNA Repair; Drug Resistance, Neoplasm; Glioblastoma; Humans; Temozolomide; Treatment Outcome
PubMed: 31068075
DOI: 10.1080/15384047.2019.1599662 -
Nucleic Acids Research May 2023The importance of non-canonical DNA structures such as G-quadruplexes (G4) and intercalating-motifs (iMs) in the fine regulation of a variety of cellular processes has...
The importance of non-canonical DNA structures such as G-quadruplexes (G4) and intercalating-motifs (iMs) in the fine regulation of a variety of cellular processes has been recently demonstrated. As the crucial roles of these structures are being unravelled, it is becoming more and more important to develop tools that allow targeting these structures with the highest possible specificity. While targeting methodologies have been reported for G4s, this is not the case for iMs, as evidenced by the limited number of specific ligands able to bind the latter and the total absence of selective alkylating agents for their covalent targeting. Furthermore, strategies for the sequence-specific covalent targeting of G4s and iMs have not been reported thus far. Herein, we describe a simple methodology to achieve sequence-specific covalent targeting of G4 and iM DNA structures based on the combination of (i) a peptide nucleic acid (PNA) recognizing a specific sequence of interest, (ii) a pro-reactive moiety enabling a controlled alkylation reaction, and (iii) a G4 or iM ligand orienting the alkylating warhead to the reactive residues. This multi-component system allows for the targeting of specific G4 or iM sequences of interest in the presence of competing DNA sequences and under biologically relevant conditions.
Topics: Alkylating Agents; Alkylation; DNA; G-Quadruplexes; Ligands; Light; Color
PubMed: 36971129
DOI: 10.1093/nar/gkad189