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Pharmacogenomics of Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Patrick Johnston, Howard L. McLeod
A primary mechanism of action of 5-FU is inhibition of the nucleotide synthetic enzyme thymidylate synthase (TS) by its active metabolite fluorodeoxyuridine monophosphate (FdUMP) resulting in thymidylate depletion, which if prolonged causes apoptosis via the so-called thymineless death (60). TS is a cytosolic enzyme that catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) to yield deoxythymidine monophosphate, a precursor of deoxythymidine triphosphate, which is required for DNA synthesis and repair (61). FdUMP forms a stable ternary complex with TS and 5,10-methylene tetrahydrofolate (CH2THF), which blocks deoxythymidine monophosphate production, thereby inhibiting DNA synthesis and repair.
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
As noted, yeast cytosine deaminase expressed by RRV-CD catalyzes intracellular conversion of the antifungal prodrug 5-FC into the anticancer drug 5-FU. The primary mechanism of action by which 5-FU exerts its cytotoxicity is inhibition of thymidylate synthase, the key enzyme in the de novo synthesis of thymidine [59]. Lack of thymidine, the only nucleotide unique to DNA, has a profound effect on actively dividing cells, ultimately resulting in ‘thymineless death’ [60]. However, quiescent cells do not require high levels of thymidine to support DNA replication, and are able to maintain DNA repair by upregulation of the salvage pathway enzyme thymidine kinase [61]. Thus, cancer cells that were previously infected during mitosis, but which then enter quiescence, would survive prodrug treatment. In fact, 5-FU inhibition of thymidylate synthase has even been reported to drive cancer cells into quiescence to escape cell death [62,63]. These infected quiescent cancer cells represent a reservoir of virus-producing cells which continue to constitutively bud off virus progeny from the integrated provirus even in quiescence, enabling viral persistence and continued viral transmission to as yet uninfected cancer cells as they resume mitosis during tumor recurrence. Notably, long-term control of tumor growth was achieved in human xenograft tumor models in immunodeficient mice, but recurrence was still observed upon cessation of prodrug treatment [38].
Bacterial death from treatment with fluoroquinolones and other lethal stressors
Published in Expert Review of Anti-infective Therapy, 2021
When bacteria are starved for most nutrients, such as carbohydrates and amino acids, they stop growing but remain alive. Starvation for thymine is unique, because cells die rapidly. Many explanations have been proposed, but each suffered from counter-examples. We found that thymine starvation elicits two events: expansion of persistent single-stranded DNA gaps and a surge in ROS accumulation. Both are necessary for DNA breakage and thymineless death. Since single-strand DNA can be a target for peroxide-mediated DNA breakage [97], an expansion of persistent DNA gaps during thymine starvation would reduce the level of peroxide needed for creation of double-stranded DNA breakage and thereby undermine the assertion that cells lack enough peroxide to self-destruct [74].
Novel heterocyclic hybrids of pyrazole targeting dihydrofolate reductase: design, biological evaluation and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ismail M. M. Othman, Mohamed A. M. Gad-Elkareem, Abd El-Galil E. Amr, Mohamed A. Al-Omar, Eman S. Nossier, Elsayed A. Elsayed
Recently, dihydrofolate reductase (DHFR) has been considered to be a universal and attractive enzyme which is present in all organisms. Its essential function is to catalyse the reduction of dihydrofolate to tetrahydrofolate within the thymidylate synthesis cycle. As a result, inhibition of DHFR causes “thymineless death”5–8. Inhibitors of DHFR explored a crucial role in medicine like methotrexate that is a non-selective inhibitor and a confirmed agent used in oncology for the treatment of rheumatoid arthritis and several cancers9. Thus, there are a vast number of interesting target profiles and literatures achievable with DHFR and its inhibitors.