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Journal of Pharmaceutical and... Jan 2023Alkylating agents were among the first anticancer drugs to be discovered and continue to be the most commonly used in chemotherapy. They are electrophiles that react... (Review)
Review
Alkylating agents were among the first anticancer drugs to be discovered and continue to be the most commonly used in chemotherapy. They are electrophiles that react with the ring nitrogen and extracyclic oxygen atoms of DNA bases, forming covalent adducts that further lead to cross-linking of DNA strands, abnormal base pairing or DNA strand breaks. The investigation and quantitative analysis of alkylating agents in biological samples are essential for monitoring the therapy progression and efficiency, understanding their pharmacokinetics and develop new more effective and specific chemotherapeutical drugs. Among biotechnological methods, electrochemical techniques are particularly important in pharmaceutical medicine, owing to their rapid detection, great sensitivity, robustness, exceptional detection limits, ability to be used with small analyte volumes in turbid biofluids, and easy adaptability to miniaturization and point-of-care (POC) testing. This article provides first an exhaustive review concerning the electrochemical methods of characterization and quantification of different classes of chemotherapeutic alkylating agents (triazenes and hydrazines, nitrosoureas, nitrogen mustards, oxazaphosphorines, alkyl alkane sulfonates and ethylene imines) in standard samples, pharmaceutical formulations and biological matrixes. The second part of the article focuses on the recent electrochemical methodologies and DNA-electrochemical biosensors developed to study the interaction of alkylating agents with DNA. These studies are relevant for obtaining real-time details about the alkylating agents' mechanism of action and for assessing the oxidative DNA damage they cause, important for the development of improved antineoplastic drugs.
Topics: Electrochemistry; Antineoplastic Agents, Alkylating; Alkylating Agents; DNA; Antineoplastic Agents; Nitrogen; Pharmaceutical Preparations
PubMed: 36244084
DOI: 10.1016/j.jpba.2022.115036 -
Trends in Biochemical Sciences Mar 2017Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are... (Review)
Review
Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so-called 'epigenetic' adducts. Here, we discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy.
Topics: Alkylation; Antineoplastic Agents, Alkylating; DNA Damage; DNA Repair; DNA, Neoplasm; Humans; Neoplasms
PubMed: 27816326
DOI: 10.1016/j.tibs.2016.10.001 -
ACS Chemical Biology Jun 2023The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other...
The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other cancers. Both agents target DNA with cyclophosphamide causing alkylation damage and doxorubicin stabilizing the topoisomerase II-DNA complex. We hypothesize a new mechanism of action whereby both agents work in concert. DNA alkylating agents, such as nitrogen mustards, increase the number of apurinic/apyrimidinic (AP) sites through deglycosylation of labile alkylated bases. Herein, we demonstrate that anthracyclines with aldehyde-reactive primary and secondary amines form covalent Schiff base adducts with AP sites in a 12-mer DNA duplex, calf thymus DNA, and MDA-MB-231 human breast cancer cells treated with nor-nitrogen mustard and the anthracycline mitoxantrone. The anthracycline-AP site conjugates are characterized and quantified by mass spectrometry after NaB(CN)H or NaBH reduction of the Schiff base. If stable, the anthracycline-AP site conjugates represent bulky adducts that may block DNA replication and contribute to the cytotoxic mechanism of therapies involving combinations of anthracyclines and DNA alkylating agents.
Topics: Humans; Anthracyclines; Schiff Bases; DNA; DNA Damage; Topoisomerase II Inhibitors; Doxorubicin; Antibiotics, Antineoplastic; Alkylating Agents; Cyclophosphamide; DNA Repair; DNA Adducts
PubMed: 37200590
DOI: 10.1021/acschembio.3c00033 -
Expert Opinion on Pharmacotherapy Aug 2017Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal... (Review)
Review
Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment. Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice. Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Interleukin-6; Melphalan; Molecular Structure; Multiple Myeloma; Myeloma Proteins; Prognosis
PubMed: 28658983
DOI: 10.1080/14656566.2017.1349102 -
Proceedings of the National Academy of... Mar 2022Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored,...
Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, knockdown cells were complemented with wild-type or with an variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation.
Topics: Alkylation; Animals; Brain Neoplasms; DNA Glycosylases; DNA Repair; Endoplasmic Reticulum Stress; Glioblastoma; Humans; Mice; Protein Unfolding; X-Box Binding Protein 1
PubMed: 35197283
DOI: 10.1073/pnas.2111404119 -
Mutation Research. Reviews in Mutation... 2015Alkylating agents, which are widespread in the environment, also occur endogenously as primary and secondary metabolites. Such compounds have intrinsically extremely... (Review)
Review
Alkylating agents, which are widespread in the environment, also occur endogenously as primary and secondary metabolites. Such compounds have intrinsically extremely cytotoxic and frequently mutagenic effects, to which organisms have developed resistance by evolving multiple repair mechanisms to protect cellular DNA. One such defense against alkylation lesions is an inducible Adaptive (Ada) response. In Escherichia coli, the Ada response enhances cell resistance by the biosynthesis of four proteins: Ada, AlkA, AlkB, and AidB. The glycosidic bonds of the most cytotoxic lesion, N3-methyladenine (3meA), together with N3-methylguanine (3meG), O(2)-methylthymine (O(2)-meT), and O(2)-methylcytosine (O(2)-meC), are cleaved by AlkA DNA glycosylase. Lesions such as N1-methyladenine (1meA) and N3-methylcytosine (3meC) are removed from DNA and RNA by AlkB dioxygenase. Cytotoxic and mutagenic O(6)-methylguanine (O(6)meG) is repaired by Ada DNA methyltransferase, which transfers the methyl group onto its own cysteine residue from the methylated oxygen. We review (i) the individual Ada proteins Ada, AlkA, AlkB, AidB, and COG3826, with emphasis on the ubiquitous and versatile AlkB and its prokaryotic and eukaryotic homologs; (ii) the organization of the Ada regulon in several bacterial species; (iii) the mechanisms underlying activation of Ada transcription. In vivo and in silico analysis of various microorganisms shows the widespread existence and versatile organization of Ada regulon genes, including not only ada, alkA, alkB, and aidB but also COG3826, alkD, and other genes whose roles in repair of alkylated DNA remain to be elucidated. This review explores the comparative organization of Ada response and protein functions among bacterial species beyond the classical E. coli model.
Topics: Alkylating Agents; Bacteria; Bacterial Proteins; DNA Repair; DNA Repair Enzymes; Evolution, Molecular; Regulon
PubMed: 25795127
DOI: 10.1016/j.mrrev.2014.12.001 -
Revue Neurologique Nov 2020Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The incidence of malignant gliomas is growing in the elderly population. Unfortunately,... (Review)
Review
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The incidence of malignant gliomas is growing in the elderly population. Unfortunately, increasing age is one of the most important negative prognostic factors for this tumor. For a long time, the treatment of elderly patients with GBM was controversial. Currently, more active strategies are the rule. Indeed, as in the younger population, prospective randomized studies have recently established the benefit of radiotherapy associated with concomitant and adjuvant chemotherapy by temozolomide in older patients suffering from malignant gliomas with good functional status. The application of chemotherapy alone may be especially useful in patients with poor functional status and O-6-methylguanine-DNA methyltransferase (MGMT) promotor methylation. For the portion of the elderly population identified as frail, treatment decisions should be made in the context of a comprehensive geriatric evaluation while also taking into account quality of life and concomitant pathologies. The willingness of the patient and his or her caregivers will also be key to the therapeutic decision. Symptomatic treatments such as corticosteroids and antiepileptic drugs may be less tolerated in this population compared to younger patients and should be used only if requested. In the future, it will be necessary to continue to develop specific schedules of treatment in the frail population. For this reason, prospective randomized clinical trials are still needed to pursue improvements in the pattern of care of malignant glioma in elderly individuals.
Topics: Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Glioblastoma; Humans; Prospective Studies; Quality of Life; Temozolomide
PubMed: 32307112
DOI: 10.1016/j.neurol.2020.01.362 -
Critical Reviews in Biochemistry and... Apr 2021DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are... (Review)
Review
DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are deeply entwined with the development of poisonous materials originally intended for use in warfare. Over the last decades, their anti-proliferative effects have focused on the specific mechanisms by which they damage DNA, and the factors involved in the repair of such damage. Due to the variety of aberrant adducts created even for the simplest alkylating agents, numerous pathways of repair are engaged as a defense against this damage. More recent work has underscored the role of RNA damage in the cellular response to these agents, although the understanding of their role in relation to established DNA repair pathways is still in its infancy. In this review, we discuss the chemistry of alkylating agents, the numerous ways in which they damage nucleic acids, as well as the specific DNA and RNA repair pathways which are engaged to counter their effects.
Topics: Alkylating Agents; Alkylation; Animals; DNA; DNA Damage; DNA Repair; Humans; RNA
PubMed: 33430640
DOI: 10.1080/10409238.2020.1869173 -
Anti-cancer Agents in Medicinal... 2022Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer... (Review)
Review
Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer cases increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to halt of DNA replication and eventual cell death. Nitrogen lone pairs of 'nitrogen mustard' produce an intermediate 'aziridinium ion' at the molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the Structure Activity Relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability.
Topics: Alkylating Agents; Antineoplastic Agents; Antineoplastic Agents, Alkylating; DNA; Humans; Leukemia; Mechlorethamine; Neoplasms
PubMed: 34382529
DOI: 10.2174/1871520621666210811105344 -
Expert Review of Molecular Diagnostics Sep 2014Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is... (Review)
Review
Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is heterogeneous across patients. Interestingly, predictive biomarkers of response to these classic chemotherapeutic agents have been identified in neuro-oncology (i.e., 1p/19q co-deletion, IDH mutation and O6-methylguanine DNA-methyltransferase promoter methylation). The most emblematic biomarker in glioblastoma is O6-methylguanine DNA-methyltransferase promoter methylation that predicts response to temozolomide. In parallel, innovative drugs are emerging. Some of these agents have shown some activity but in a limited number of glioblastoma patients. One of the major challenges is to identify molecular predictors of response to these smart drugs for an efficient personalized medicine. These novel agents have been tested in clinical trials enrolling glioblastoma patients. Although none of them has been validated prospectively in Phase III clinical trials, interesting molecular predictors of response to these drugs have been investigated and are presented in this review, which also reports more advanced biomarkers.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; Dacarbazine; ErbB Receptors; Glioblastoma; Humans; Molecular Targeted Therapy; O(6)-Methylguanine-DNA Methyltransferase; Promoter Regions, Genetic; Temozolomide
PubMed: 25096963
DOI: 10.1586/14737159.2014.945436