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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
Based on the above, the relatively low occurrence of cytotoxic effects associated with cyclophosphamide may be explained by the relatively high concentration of ALDH-like enzymes in bone marrow stem cells, liver cells, and the intestinal epithelium which protects these actively proliferating tissues from the toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to the relatively nontoxic carboxy-phosphamide and 4-ceto-cyclophosphamide (Figure 5.20).
High-Dose Immune Suppression without Hematopoietic Stem Cells for Autoimmune Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
The unique pharmacology of cyclophosphamide accounts for its potent immunosuppressive properties and its ability to spare hematopoietic stem cells. Cyclophosphamide is a pro-drug that is converted in the liver to 4-hydroxycyclophosphamide and its tautomer aldophosphamide (Fig. 1). Aldophosphamide diffuses freely into the cell and is converted to the active compound phosphoramide mustard, or inactivated by aldehyde dehydrogenase to form carboxyphosphamide.17-19 Lymphoid cells, including natural killer cells, B and T lymphocytes, have low levels of aldehyde dehydrogenase and are rapidly killed by high doses of cyclophosphamide. Interestingly, primitive hematopoietic stem cells possess high levels of aldehyde dehydrogenase rendering them highly resistant to cyclophosphamide.17-19 Although the CD34 pool is markedly reduced in severe aplastic anemia, the high response rate in aplastic anemia to immunosuppressive therapy attests to the fact that healthy hematopoietic stem cells remain in most cases of aplastic anemia.
A Review on Medicinal Plants used in Cardioprotective Remedies in Traditional Medicine
Published in Anne George, Oluwatobi Samuel Oluwafemi, Blessy Joseph, Sabu Thomas, Sebastian Mathew, V. Raji, Holistic Healthcare, 2017
Cyclophosphamide (CP) is widely used as an antineoplastic and immunosuppressant agent. It is used for the treatment of chronic and acute leukemias, multiple myeloma, lymphomas, rheumatic arthritis and as immunosuppressive agent for bone marrow transplantation. High dose CP associated cardiotoxicity occurs within 10 d of its administration.78 The two active metabolite of CP are phosphoramide mustard and acrolein. CP is activated by hepatic P450 enzyme. The major active circulating metabolite called 4-hydroxycyclophosphamide is generated by hydroxylation, which is converted intracellularly to aldophosphamide. Aldophosphamide is metabolized to phosphoramide mustard and acrolein. Of these, phosphoramide mustard is associated with therapeutic effect of CP, while, acrolein is believed to be responsible for its cytotoxic effects. The mechanism underlying CP induced cardiotoxicity is associated with generation of free radicals by these metabolites.22 CP induced oxidative stress disrupts the inner mitochondrial membrane of heart leading to the permeability of calcium ions (Table 11.6).79
Hippocampal neuroinflammation following combined exposure to cyclophosphamide and naproxen in ovariectomized mice
Published in International Journal of Neuroscience, 2023
Samantha Pavlock, Deirdre M. McCarthy, Anisha Kesarwani, Pascal Jean-Pierre, Pradeep G. Bhide
Naproxen and aldophosphamide, the active metabolite of CP, share a binding site on serum albumin.38 Naproxen binds with a higher affinity than aldophosphamide.38 Therefore, when CP and naproxen are both present, naproxen displaces aldophosphamide from the binding site, leading to an increase in unbound, free aldophosphamide in the serum. Since aldophosphamide crosses the blood brain barrier, it likely increases neuroinflammation.38 Therefore, in the presence of naproxen, the effects of CP on inflammation may have been augmented. One implication of this finding is that naproxen may not be a suitable anti-inflammatory drug to address neuroinflammation produced by CP. However, NSAIDs as a class have significant beneficial effects in multiple cancers due to their ability to reduce cell proliferation, induce apoptosis, and sensitize cancer cells to the anti-proliferative actions of chemotherapy drugs [Review in Hilovska et al. (2015)8] Therefore, combining naproxen with CP likely will produce other benefits even if it did not reduce neuroinflammation. In addition, as mentioned earlier, beginning naproxen exposure after CP exposure and continuing naproxen for a longer period, perhaps after CP exposure has ended, may improve the benefit profile of naproxen. Future studies will address these possibilities.
Enhanced immunization techniques to obtain highly specific monoclonal antibodies
Published in mAbs, 2018
Rodrigo de Almeida, Cecília Naomi Nakamura, Marina de Lima Fontes, Elenice Deffune, Sérgio Luis Felisbino, Ramon Kaneno, Wagner José Fávaro, Athanase Billis, Marcel Otavio Cerri, Ana Marisa Fusco-Almeida, Maria José Mendes Giannini, Andrei Moroz
The subtractive immunization technique, induced by drug, has proved its efficiency in the production of antibodies capable of recognizing desired cell types that have high similarity with other cell types, and reducing the production of undesirable antibodies (e.g., antibodies that cross-react with other cells). Matthew and Sandrock13 first proposed the use of cyclophosphamide (Cy) as a modulator of the immune response, also envisioning that this drug could be used as a key aspect in a subtractive immunization approach, specifically for the production of mAbs. Cy is an immunosuppressive drug that, given its classical anti-proliferative action, eliminates the B and T lymphocytes that initiate clonal proliferation after exposure to a set of antigens. Cy is not a reactive compound when delivered to the mice; initially is must be activated in the body, via cytochrome P450 oxidation at the liver, which results in the formation of 4-hydroxycyclophosphamide and its aldophosphamide tautomer. Next, the 4-hydroxycyclophosphamide/aldophosphamide enters target cells by diffusion, releasing aldophosphamide inside the cell. This compound then spontaneously decomposes to produce phosphoramide mustard, the first alkylating agent produced in the metabolism of cyclophosphamide, which will ultimately eliminate the targeted cells.14
Intracellular activation of 4-hydroxycyclophosphamide into a DNA-alkylating agent in human leucocytes
Published in Xenobiotica, 2021
Minghan Yong, Kathryn Elisa Burns, Janak de Zoysa, Nuala Ann Helsby
Cyclophosphamide is a prodrug and requires enzymatic bioactivation (reviewed in Emadi et al. 2009; Helsby et al. 2019 ). This occurs via hydroxylation to 4-hydroxycyclophosphamide (4-OHCP), which is catalysed primarily by the hepatic cytochrome P450 enzymes CYP2B6, CYP2C19, and to a lesser extent CYP3A4. Importantly, 4-OHCP exists in an equilibrium with aldophosphamide, its open-ringed tautomer (Figure 1). Aldophosphamide can then either (a) be detoxified by aldehyde dehydrogenase 1A1 (ALDH1A1) to form the inactive metabolite carboxyphosphamide, or (b) undergo conversion into the DNA alkylating agent phosphoramide mustard (PAM) with formation of the by-product acrolein.