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Biological Response Modifiers and Chemotherapeutic Agents that Alter Interleukin 2 Activities
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
William L. West, Allen R. Rhoads, Clement O. Akogyeram
In addition to cyclophosphamide, many active metabolites such as 4-hydroxycyclophosphamide, aldophosphamide, phosphoramide mustard, acrolein, and possibly nornitrogen mustard are believed to have both antineoplastic and immunosuppressive effects. Alkylating agents in general are known to be cytotoxic to lymphocytes by alkylating nucleic acids and forming cross-links between macromolecules (polypeptide or polynucleotide chains) with relatively stable bonds. In addition, they are known to inhibit protein and nucleic acid (DNA) biosynthesis, and to selectively alkylate purine bases, which not only results in depurination but also introduces errors during transcription and replication.
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.
Clinical Pharmacodynamics of Anticancer Drugs
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Howard L. McLeod, William E. Evans
The alkylating agent cyclophosphamide is an active agent in the treatment of hematologic malignancies and solid tumors, and is a common component of preparative regimens for BMT. Cyclophosphamide is not directly cytotoxic, but rather undergoes hydroxylation by hepatic microsomal mixed-function oxidases to 4-hydroxycyclophosphamide. 4-Hydroxycyclophosphamide exists in equilibrium with aldophosphamide which is either converted to acrolein and the active cytotoxic metabolite phosphoramide mustard, or oxidation to the inactive carboxyphosphamide.
Drug metabolising enzyme polymorphisms and chemotherapy-related ovarian failure in young breast cancer survivors
Published in Journal of Obstetrics and Gynaecology, 2021
Lindsey M. Charo, Michael V. Homer, Loki Natarajan, Carolyn Haunschild, Karine Chung, Jun J. Mao, Angela M. DeMichele, H. Irene Su
Cyclophosphamide is a common chemotherapy in breast cancer treatment. It intercalates DNA in a non-cell cycle specific manner, potentially damaging both growing and non-growing ovarian follicles (Warne et al. 1973). Cyclophosphamide requires activation by several cytochrome P450 enzymes. P450 enzymes activate cyclophosphamide through hydroxylation to the cytotoxic form 4-hydroxycyclophosphamide (Figure 1) (Scripture et al. 2005). This cytotoxic form is then inactivated by glutathione S-transferase enzymes through glutathione conjugation (Choi et al. 2006). There is known genetic variation in these enzymes, many of which are associated with variable protein expression (de Morais et al. 1994; Kuehl et al. 2001; Lang et al. 2001; Takada et al. 2004). These functional single nucleotide polymorphisms (SNPs) in drug metabolising enzymes have been associated with cancer-related outcomes, such as recurrence and survival (Sweeney, Mcclure, et al. 2000; Ambrosone et al. 2001; Sweeney et al. 2003; DeMichele et al. 2007; Gor et al. 2010).
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.