Diet and Cancer Prevention
James M. Rippe in Lifestyle Medicine, 2019
Folate is a water-soluble B vitamin, so called because it is abundant in foliage (green leafy vegetables). Folic acid, the synthetic form of folate, is used to fortify manufactured cereal products, flours, grains, and spreads. The relationship between dietary folate and cancer serves as an important example of the significance of the timing of exposure and diet-gene interactions. The mechanisms by which dietary folate can influence cancer development are related to the sole biochemical function for folate—mediating the transfer of one-carbon units. In this role, folate is an important factor in DNA synthesis, stability, integrity, and repair. If dietary folate is limited, the balance of purine and pyrimidine DNA precursors is altered, and normal DNA repair is inhibited. Moreover, uracil, which is not normally present in DNA, is mis-incorporated into the DNA molecule in place of thymidine, resulting in DNA strand breakage, chromosomal damage, and malignant transformation. Furthermore, cytosine methylation is altered, leading to global DNA hypomethylation and/or changes in gene-specific methylation and inappropriate protooncogene activation. A growing body of evidence from cell culture, animal, and human studies indicates that folate deficiency is associated with DNA strand breaks, impaired DNA repair, and increased mutations, and that folate supplementation can correct some of these defects induced by folate deficiency.
Genomic Instability During Aging of Postmitotic Mammalian Cells
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Hydroxymethyluracil is an oxidation product of thymine, and uracil is the deamination product of cytosine. It has been suggested that deamination of deoxycytidine is a common event in the genome of a mammalian cell at 37°C.44,55,63 The work of Ames and others,132–135 moreover, has shown that oxidation damage to mammalian DNA can be extensive for some cells. Therefore, it is surprising that Kirsh et al.151 failed to detect deoxyuridine or 5-hydroxymethyldeoxyuridine in DNAs from various tissues of mice ranging in age from 7 to 31 months. The absence of altered deoxynucleosides in somatic cell DNA implies exceedingly efficient repair of these lesions. This investigation employed reversed-phase HPLC separation of deoxynucleosides, coupled with UV-detection/quantification.151 The limits of detection corresponded to approximately 10 pmol of modified deoxynucleosides per micromole of normal deoxynucleosides, or 1 modification per 105 residues. To compare this method with those that were used to measure indigenous methyl adducts128 and oxidative damage,133,135 one can estimate that UV detection is 10- to 20-fold lower than electrochemical detection, depending on the electrochemical activity of the individual base or deoxynucleoside. Therefore if background, steady-state levels of deoxyuridine and 5-hydroxymethyldeoxyuridine in DNA are similar to those for 7-methylguanine or 8-hydroxdeoxyguanosine, minimum detection limits of 1 × 10-6 will be required to measure them.
Systemic therapy for appendiceal cancer
Wim P. Ceelen, Edward A. Levine in Intraperitoneal Cancer Therapy, 2015
Among antineoplastic agents, 5-fluorouracil belongs to the class of antimetabolites. More specifically, it is a fluorinated analog of the pyrimidine uracil that interferes with both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) syntheses [21]. 5-Fluorouracil is a prodrug that must be converted via dehydrogenase enzymes to its active metabolites fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (F-UTP). F-dUMP is thought to be the more active metabolite with regard to cytotoxicity because of its ability to tightly bind and interfere with thymidylate synthase (TS). With the inhibition of TS, thymidine cannot be formed from uracil, arresting this essential step in DNA synthesis. In contrast, the metabolite F-UTP exerts its mechanism of action on RNA. It is directly incorporated, in place of uracil, as an RNA base pair, halting RNA activity and synthesis [21].
Identifying novel drugs with new modes of action for neglected tropical fungal skin diseases (fungal skinNTDs) using an Open Source Drug discovery approach
Published in Expert Opinion on Drug Discovery, 2022
Wilson Lim, Annelies Verbon, Wendy van de Sande
The synthetic pyrimidine 5-flucytosine (5-fluorocytosine) is the most common antifungal targeting the DNA and RNA biosynthesis pathway. It acts as a competitive antimetabolite for uracil in RNA and thymidine in DNA biosynthesis (figure 2) [124]. Despite 5-flucytosine’s success in treating invasive aspergillosis and candidemia, this compound showed limited inhibitory activity for most causative agents of the fugal skinNTDs [5, 8, 79]. The efficacy of 5-flucytosine as a single agent is limited because of prevalence of intrinsic resistant strains and frequent development of resistance during treatment. Therefore it is usually combined with amphotericin B in treating aspergillosis and candidiasis [124]. 5-flucytosine has been used in combination with amphotericin B in treating chromoblastomycosis and sporotrichosis with success, however its use in sporotrichosis had to be discontinued due to serious adverse reactions [5, 14]. Because of 5-flucytosine’s hepatoxicity, side effects and limited activity, its use in treating eumycetoma and chromoblastomycosis is not recommended.
A novel anticancer chromeno-pyrimidine analogue inhibits epithelial-mesenchymal transition in lung adenocarcinoma cells
Published in Toxicology Mechanisms and Methods, 2021
Venkateswarareddy Nallajennugari, Sankar Pajaniradje, Srividya Subramanian, Suhail Ahmad Bhat, Parthasarathi D, Savitha Bhaskaran, Syed Ali Padusha M, Rukkumani Rajagopalan
Since 1985, lung cancer has been the most common cancer (Parkin et al. 1993). As of 2018, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths) in both sexes in the world (Bray et al. 2018). Over half of the people diagnosed with lung cancer die within one year of diagnosis, and the 5-year survival is less than 18%, indicating poor lung cancer prognosis (Zappa and Mousa 2016). Cytotoxic nucleoside analogues and nucleobases were some of the first chemotherapeutic agents introduced for the medical treatment of cancer (Galmarini et al. 2002). Uracil is a naturally occurring pyrimidine nucleobase, and 5-fluorouracil is one of the earliest, most widely used, and extensively studied pyrimidine analogues. In many studies, it was observed that uracil and 5-fluorouracil (5-FU) more preferably concentrate into tumor cells than other pyrimidine bases (Shirasaka 2008). Hence, the available literature related to the action of 5-FU in cancers, has to be considered while analyzing the anticancer mechanisms of promising pyrimidine analogues.
Recent developments of RNA-based vaccines in cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2021
Elnaz Faghfuri, Farhad Pourfarzi, Amir Hossein Faghfouri, Mahdi Abdoli Shadbad, Khalil Hajiasgharzadeh, Behzad Baradaran
Sequence engineering of the ORF and UTRs regions can significantly enhance the mRNA’s expression. For instance, enriching the guanine/cytosine (GC content), or selecting the UTRs of natural enduring mRNAs can manipulate the mRNA’s expression [19]. Moreover, more appealing strategies have been proposed, e.g., the construction of circular-engineered RNAs that are resistant to exonucleases [20]. The co-assembly of mRNA and eIF4E proteins with synthetic polyamines substantially up-regulates the translation efficiency compared to mRNA alone. The underlying reason could be associated with the longer durability and attachment of these complexes to the ribosomes [21]. WO 02/098443 (CureVac GmbH) project has suggested a strategy to optimize mRNAs’ coding sequence. It describes options for substituting adenine and uracil nucleotides in the mRNA structure to enrich its G/C content. This technique can be applied to cancer therapy. In line with it, WO 2007/035355 project has proposed another strategy to increase mRNA translation. It explains how long poly(A) sequences (especially longer than 120 bp) and the combination of at least two 3′ UTRs of the beta-globin gene can increase the mRNA stability and translation capacity [22].