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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Bone marrow suppression is the most problematic side effect associated with melphalan and leads to a decreased white blood cell count with increased risk of infection. The resulting decreased platelet count can also increase the risk of bleeding. As with most cytotoxic agents, other common side effects include GI symptoms such as nausea, vomiting, and oral ulceration. Less common side effects include severe allergic reactions, cardiac arrest, interstitial pneumonitis and pulmonary fibrosis (which scars the lung tissue and can be fatal after prolonged use), hair loss, and skin reactions (e.g., rash and itching). Dosing must be reduced in the case of renal impairment, and melphalan should be avoided in breastfeeding. Contraception should be used in both men and women during treatment.
Agents for Microsphere Incorporation: Physicochemical Considerations and Physiological Consequences of Particle Embolization
Published in Neville Willmott, John Daly, Microspheres and Regional Cancer Therapy, 2020
From the aforementioned analysis it is clear that there is a complementarity between the ischemia-inducing properties of microspheres and the class of compounds known to be preferentially cytotoxic to hypoxic cells. Under optimal conditions in vitro such compounds require from 10- to 100-fold lower concentrations for equivalent cytotoxicity toward hypoxic cells compared with their aerobic counterparts.45 Although therapeutic approaches based on this class of compounds arenovel, their locus of action is still considered to be DNA.45,46 A factor limiting their use as single agents is that hypoxic cells are generally a minority of the clonogenic cells of a solid tumor and the remaining aerobic cells are resistant. One approach to this problem is the combination of hypoxia-selective cytotoxins with treatments that, by rendering the tumor ischemic, increase the proportion of sensitive hypoxic tumor cells. Indeed, it has been concluded on theoretical grounds that, provided an efficient hypoxia-selective cytotoxin is available, the more hypoxia, the better.47
Clostridioides difficile
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
Diagnostic tests for C. difficile include detection of glutamate dehydrogenase (GDH), which is an enzyme produced by C. difficile, detection of toxin A and B (Tox A/B) or a nucleic acid amplification test (NAAT) for detection of the toxin gene. Reference tests are toxigenic culture or cytotoxin assay. These tests require specialized laboratories and are time consuming. A positive GDH EIA alone will only tell you that the patient is colonized with C. difficile.
Nuclease activity: an exploitable biomarker in bacterial infections
Published in Expert Review of Molecular Diagnostics, 2022
Javier Garcia Gonzalez, Frank J. Hernandez
On the one hand, numerous plasmid and chromosomally encoded toxins involved in bacterial warfare classified in various toxin systems have been described. Among others, these include experimentally well-characterized classical toxin systems, such as bacteriocins (e.g colicins, pyocins or klebicins) [52–54] as well as a vast array of polymorphic toxin systems identified in silico across major bacterial lineages [55–57]. Interestingly, both classical bacteriocins and polymorphic toxins are known to share a number of common features. First, these toxins share different degrees of domain homology and a modular domain structure. N-terminal domains serve regulatory functions, such as trafficking, while the C-terminal domains contain the active cytotoxic domains, which can display diverse types of nuclease activity that include DNase, mRNase and tRNase. As such, these toxins tend to exert their cytotoxic functions by tampering with the flow of information inside the target cell, either by degrading nucleic acids involved in protein synthesis or by direct destruction of the genomic material. Of interest, both of these types of toxins possess co-transcribed immunity pair proteins that avoid self-intoxication and keep the toxins inactive until their delivery into the target [52–54,56].
Tracing the origins of extracellular DNA in bacterial biofilms: story of death and predation to community benefit
Published in Biofouling, 2021
Davide Campoccia, Lucio Montanaro, Carla Renata Arciola
Analogous cytotoxins have been identified in other pathogens. For instance, in P. aeruginosa, rhamnolipid has been reported to determine the lysis of neutrophil cells by acting as a biosurfactant ( Van Gennip et al. 2009). The ExoU cytotoxin and exolysin (ExlA) have also been described as two important exotoxins of P. aeruginosa (Tamura et al., 2004; Basso et al. 2017). Other examples of toxins expressed by other pathogens and capable of causing host cell death include the α-hemolysin of E. coli, the cytolysin of Vibrio cholerae, and the listeriolysin O of Listeria monocytogenes (Steinmoen et al. 2002). The action of cytolytic, necrotizing or pro-apoptotic mechanisms/factors can result in cell death and contribute to the release of substantial quantities of nucleic acids.
Hemolysin BL from novel Bacillus toyonensis BV-17 induces antitumor activity both in vitro and in vivo
Published in Gut Microbes, 2020
Jiajia Chen, Shoukui Hu, Dengbo Ji, Zhaoya Gao, Hanyang Wang, Yong Yang, Yongkang Chen, Jin Gu
Bacterial toxins are important metabolites, which were used as a cancer treatment a 100 years ago, that often have powerful cytotoxicity and incite strong immune responses toward the host. In 1910, William Coley utilized Streptococcus erysipelas and Bacillus prodigiosus to successfully treat patients with inoperable sarcomas, these are known as Coley’s toxins today. Among 52 cancer patients who received bacterial toxins treatment, 36 cases had partial responses or complete responses.7 The mechanisms by which these beneficial effects occurred are partially due to the combination of the direct cytotoxic effect of the toxins and the activation of anti-tumor immune responses. With the development of biotechnology, a growing number of researchers are trying to use bacteria and their toxins to treat advanced cancers. In 1990, the live attenuated Mycobacterium bovis (Bacillus Calmette-Guérin, BCG) was approved as a treatment for bladder cancer.8 The best-known bacterial toxins with antitumor activity are anthrax toxin, Pseudomonas aeruginosa exotoxin A, and diphtheria toxin.9,10 By conjugating the toxin to antibodies or ligands, the engineered toxins could then selectively recognize cancer cells through surface antigens or receptors. These are known as immunotoxins and were much better tolerated by animals and have since been widely tested in human clinical trials.11