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Antineoplastic Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Cyclophosphamide (Cytoxan, Neosar), an alkylating agent, is metabolized mainly by the liver to several active alkylating metabolites (phosphoramide mustard and acrolein) that cause tumor cell DNA crosslinking. Cyclophosphamide is used to treat several types of cancer, including (1) certain forms of acute and chronic leukemia, (2) ovarian, (3) multiple myeloma, (4) mycosis fungoides, and (5) breast carcinoma. It has also been used in treatment of cancers of the bladder, cervix, colorectum, endometrium, Ewing’s sarcoma, head and neck, lymphomas, kidney, lung, osteosarcoma, pancreas, and trophoblastic tumors.
Respiratory, endocrine, cardiac, and renal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Cyclophosphamide is an alkylating agent, but is an inactive prodrug, which has to be metabolised into cytotoxic metabolites. Cytochromes P450 hydroxy-late cyclophosphamide to 4 hydroxy-cyclophosphamide. Subsequent metabolites include mustard phosphoramide (cytotoxic) and acrolein. Part of the 4 hydroxy-cyclophosphamide and its tautomer, the adophosphamide, are transformed into inactive metabolites, mainly carboxyphosphamide, by aldehyde deshydrogenase. The mustard phosphoramide is the only metabolite which displays alkylating properties and is responsible for the cytotoxic antitumour activity. Acrolein is responsible for bladder toxicity.
New Biological Targets for the Treatment of Leishmaniasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran, Agostino Cilibrizzi
The nitroaromatic group has specifically been incorporated in the molecules as the trigger for this reductive activation. The reduction of the nitro group to the corresponding hydroxylamine derivative, by the NTR catalyzed reaction, leads to the fragmentation of the structure and consequent release of the requisite toxic moieties (e.g., mustards, nitro radical anions and hydroxylamine-based species) (Chen and Hu 2009). Overall, compounds 35a–c and 36a, b (Figure 26) resulted potent trypanocidal agents, although phosphoramide derivatives with a linear chain had a better inhibition profile against L. major(Hu et al. 2011). Therefore, Hu and collaborators propose to leverage the activity of NTR leishmanial isoform for drug development in two ways: (1) as an activator of new nitroaromatic/quinone-based prodrugs, (2) through the use of modulators for this enzyme target. These two approaches could also be complementary in a combined targeting strategy. For instance, L. major strains showing resistance to drug inhibitors of LmNTR (i.e., L. major nitroreductase, a flavin mononucleotide-containing nitroreductase) could theoretically be sensitive or even hypersensitive to prodrugs, which would therefore be activated by this leishmanial enzyme (Chen and Hu 2009).
Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules
Published in Drug Delivery, 2023
Ashif Iqubal, Abul Kalam Najmi, Shadab Md, Huda Mohammed Alkreathy, Javed Ali, Mansoor Ali Syed, Syed Ehtaishamul Haque
Cyclophosphamide CP) is among the most extensively and explicitly used anticancer drugs in various types of solid tumors and hematological malignancies. Apart from being a commonly used anticancer drug, it is also an immunosuppressive agent and uses in nephrotic syndrome (Hu et al., 2022). Pharmacokinetically, it is a prodrug and hence undergoes hepatic metabolism. In the liver, CP is acted upon by CYP34A and converted into phosphoramide mustard and acrolein. Phosphoramide mustard acts as an active metabolite and exhibits a potent anticancer effect via binding to N-7 of the guanine residue and altering DNA replication (Barnett et al., 2021). Acrolein, another active metabolite of CP, a small-length carbon chain and is hydrophobic in nature. Acrolein and other metabolites, such as hydroxyphosphamide, are reported to exhibit deleterious effects on various organs. Thus. When CP is administered for therapeutic purposes, it also exhibits significant toxicity, apart from its anticancer effect (Mills & Roberts, 1979). This often limit its widespread use and negatively affect patients’ quality of life. Among the various toxic manifestations of CP, nephrotoxicity is commonly observed at the therapeutic dose (Ayza et al., 2022). The kidney is an essential vital organ that regulates intracellular and extracellular physiological functions. In other words, the kidney maintains the ionic gradient, pH, fluidity, and overall body homeostasis. Thus, any alteration in kidney function directly affects the body’s overall function (Ayza et al., 2022).
Immune Response and Safety of Viral Vaccines in Children with Autoimmune Diseases on Immune Modulatory Drug Therapy
Published in Expert Review of Vaccines, 2020
Hiu Nam Tse, Ray Borrow, Peter D. Arkwright
Azathioprine (AZA), 6-mercaptopurine (MCP), mycophenolate mofetil (MMF), methotrexate (MTX), and leflunomide are antimetabolites that inhibit de novo DNA synthesis. Active drug metabolites inhibit Rac-1 activities by binding GTPases, which then leads to mitochondrial-driven T-cell apoptosis. 6-thio-GTP also triggers T-lymphocytes apoptosis by inhibiting CD28, a co-stimulatory signal that is required for T-cell activation [4,10]. Mycophenolate mofetil (MMF) inhibits purine metabolism and blocks inosine monophosphate dehydrogenase (IMPDH) and thus DNA replication [4]. Leflunomide blocks de novo pyrimidine synthesis. Activated T- and B-cells are arrested in the G1 phase of the cell cycle, inhibiting T-cell proliferation and B-cell antibody production [11]. MTX inhibits both purine and pyrimidine synthesis by blocking several key enzymes in de novo DNA synthesis [12]. It is also a folate antagonist and increases adenosine, activating an intracellular cascade that promotes an anti-inflammatory response [13]. Cyclophosphamide (CYCLO) is an alkylating agent that inhibits protein synthesis through DNA and RNA crosslinking after being metabolized to aldophosphamide and then phosphoramide and acrolein. Phospharamide cross-links adjacent DNA strands, inhibiting T- and B-cell proliferation [14].
Evaluation of mutagenic and anti-mutagenic potential of alpha-lipoic acid by chromosomal aberration assay in mice
Published in Drug and Chemical Toxicology, 2020
Rina Tripathi, David Banji, Pankaj Tripathi
CP was the positive control in this study. It is a covalent DNA binding agent (Jackson et al. 1996). Its cytotoxicity and genotoxicity have been reviewed and updated earlier (Anderson et al. 1995). CP can be a positive control chemical in genetic toxicity tests (Krishna et al. 1995). It can also be a reference standard to induce cyto/genotoxicity and determine the anti-mutagenic effects of synthetic and herbal drugs (Tripathi et al. 2012, 2013a,b, 2014). The therapeutic and toxic effects of CP require metabolic activation. CP is activated by hepatic microsomal CYP450 to 4-hydroxycyclophosphamide (4-OHCP) that converts it to aldophosphamide which spontaneously further decomposes to DNA cross-linking agent: phosphoramide mustard and acrolein (Habibi et al. 2015, Kour et al. 2017). CP’s antineoplastic effects are associated with phosphoramide mustard whereas acrolein is linked with toxic side effects (Kern and Kehrer 2002). Acrolein interferes with the tissue antioxidant defense system (Arumugam et al. 1997) to produce highly reactive oxygen free radical (Mythili et al. 2004). This suppresses superoxide dismutase, GSH peroxidase, and catalase activities (Dumontet et al. 2001) and is mutagenic to mammalian cells (Kawanishi et al. 1998). The induction of significantly (p < 0.005) higher percentages of CAs (including and excluding gaps) by CP (40 mg/kg b.w. of mice) seen here agrees well with its earlier reported clastogenicity.