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Mechanisms of Anticancer Drugs
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Methotrexate competitively inhibits dihydrofolate reductase, which is responsible for the formation of tetrahydrofolate from dihydrofolate. This is essential for the generation of a variety of coenzymes that are involved in the synthesis of purines, thymidylate, methionine and glycine. A critical influence on cell division also appears to be inhibition of the production of thymidine monophosphate, which is essential for DNA and RNA synthesis. The block in activity of dihydrofolate reductase can be bypassed by supplying an intermediary metabolite, most commonly folinic acid. This is converted to tetrahydrofolate that is required for thymidylate synthetase function (Figure 4.2).
Case 15
Published in Atul B. Mehta, Keith Gomez, Clinical Haematology, 2017
Administration of folic acid without B12 therapy can lead to worsening of the neurological changes. B12 is a coenzyme for methionine synthase, a reaction needed to activate folate by converting it from methyl tetrahydrofolate (me-THF) to THF. The reaction is linked to the demethylation of methionine to homocysteine, and emphasises the role of B12 and folate metabolism in reducing homocysteine levels and improving cardiovascular risk. Folate is a coenzyme for the synthesis of thymidine monophosphate (TMP); deficiency of B12 and folate therefore leads to impaired DNA synthesis.
Pharmacokinetics of intraperitoneal cytotoxic drug therapy
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Since their introduction in 1957 by Heidelberger et al., the fluorinated pyrimidines have been successfully used for a wide variety of tumors and are still an essential component of all successful gastrointestinal cancer chemotherapy regimens [84,85]. This thymidylate synthase inhibitor binds covalently with the enzyme and prevents the formation of thymidine monophosphate, the DNA nucleoside precursor. Also 5-FU by its metabolites 5-fluoro-uridine diphosphate and 5-fluoro-uridine triphosphate gets incorporated in RNA, resulting in a second cytotoxic pathway. The action of 5-fluorouracil is therefore cell-cycle-specific. These characteristics limit the use of IP 5-fluorouracil to EPIC [86–89]. Minor augmentation of 5-fluorouracil by mild hyperthermia is reported [31]. 5-Fluorouracil is not chemically compatible with other drugs in a mixed solution for infusion or instillation.
Capecitabine in treating patients with advanced, persistent, or recurrent cervical cancer: an active and safe option?
Published in Expert Opinion on Drug Safety, 2021
Federica Tomao, Giuseppe Caruso, Lucia Musacchio, Violante Di Donato, Maria Cristina Petrella, Monica Verrico, Silverio Tomao, Pierluigi Benedetti Panici, Ludovico Muzii, Innocenza Palaia
Capecitabine is an oral pro-drug that is enzymatically metabolized by thymidine phosphorylase (TP) to cytotoxic 5-fluorouracil (5-FU). The latter inhibits thymidylate synthase (TS) and thus the synthesis of thymidine monophosphate (dTMP), the active form of thymidine required for DNA de novo synthesis [30]. The dihydropyrimidine dehydrogenase (DPD) is another enzyme involved in the 5-FU metabolic pathway, which catabolizes 5-FU to inactive dihydrofluorouracil in the liver, resulting in increased urinary excretion (Figure 1) [31]. Basically, the TP/DPD ratio biologically determines the intracellular 5-FU concentration [32]. Extensive studies have associated both profound and partial DPD deficiency (3–5% of the general population) with severe, unanticipated toxicities after 5-FU administration, including mucositis, hair loss, diarrhea, neutropenia, skin rash, and neurologic toxicities [33]. Research on the molecular basis behind DPD deficiency has highlighted various sequence variants of the DPYD gene, hence screening patients for DPD deficiency prior to 5 FU or capecitabine administration should be recommended [34].
1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yanlin Jian, Martijn D. P. Risseeuw, Mathy Froeyen, Lijun Song, Davie Cappoen, Paul Cos, Hélène Munier-Lehmann, Serge van Calenbergh
Thymidine monophosphate kinase (TMPK), an enzyme at the junction of the de novo (involving thymidylate synthase) and salvage pathway, is responsible for the conversion of thymidine monophosphate (TMP) to thymidine diphosphate (TDP)5,6. Further phosphorylation leads to the formation of thymidine triphosphate (TTP), which is indispensable for DNA synthesis7. Mycobacterium tuberculosis TMPK (MtbTMPK) shows low (22%) sequence identity with the human isozyme and has a unique catalytic mechanism8,9, further supporting it as an attractive target for developing new anti-TB drugs. Both industrial and academic efforts have afforded several potent MtbTMPK inhibitors in the past two decennia10–19, including thymidine-like and non-nucleoside inhibitors (Figure 1)20–24.
Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Mehdi Soleymani-Goloujeh, Ali Nokhodchi, Mehri Niazi, Saeedeh Najafi-Hajivar, Javid Shahbazi-Mojarrad, Nosratollah Zarghami, Parvin Zakeri-Milani, Ali Mohammadi, Mohammad Karimi, Hadi Valizadeh
Methotrexate (MTX) is a chemotherapy agent and immune system suppressant which acts as an antagonist of folate. This drug competitively inhibits dihydrofolate reductase (DHFR) and finally affects the production of thymidine monophosphate, which is essential for DNA and RNA synthesis [12]. Aiming to consolidate this research process, loading MTX on desired CPP sequences due to delivery to MCF-7 human breast adenocarcinoma cancer cells was carried out in two different patterns; the physical linkage between drug molecules and desired peptides (modified or unmodified sequences) and also chemical conjugation of drug molecules to CPPs. Finally, cell viability and cytotoxicity of blank carriers (e.g. peptide alone), cell viability and cytotoxicity of drug loaded CPPs; both physically linked and chemically conjugated sequences were assessed by3–(4, 5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay. In the uptake studies, three groups of peptides were chosen and uptake studies were carried out by flow cytometry, fluorescent microscopy, live cell imager and confocal laser scanning microscope (CLSM).