Standing the test of time: targeting thymidylate biosynthesis in cancer therapy

Abstract

Over the past 60 years, chemotherapeutic agents that target thymidylate biosynthesis and the enzyme thymidylate synthase (TS) have remained among the most-successful drugs used in the treatment of cancer. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, and antifolates, such as methotrexate and pemetrexed, induce a state of thymidylate deficiency and imbalances in the nucleotide pool that impair DNA replication and repair. TS-targeted agents are used to treat numerous solid and haematological malignancies, either alone or as foundational therapeutics in combination treatment regimens. We overview the pivotal discoveries that led to the rational development of thymidylate biosynthesis as a chemotherapeutic target, and highlight the crucial contribution of these advances to driving and accelerating drug development in the earliest era of cancer chemotherapy. The function of TS as well as the mechanisms and consequences of inhibition of this enzyme by structurally diverse classes of drugs with distinct mechanisms of action are also discussed. In addition, breakthroughs relating to TS-targeted therapies that transformed the clinical landscape in some of the most-difficult-to-treat cancers, such as pancreatic, colorectal and non-small-cell lung cancer, are highlighted. Finally, new therapeutic agents and novel mechanism-based strategies that promise to further exploit the vulnerabilities and target resistance mechanisms within the thymidylate biosynthesis pathway are reviewed.

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

“…e Some drugs, such as abacavir and flucloxacillin, elicit immunemediated toxicity reactions by binding to specific variants of the major histocompatibility complex either directly or conjugated to a protein carrier as a hapten, which in turn facilitates activation of T cells and triggers an immune response represent the first-line treatment for various solid tumors. Fluorouracil (5FU) and other fluoropyrimidines, such as capecitabine, tegafur, and floxuridine, inhibit thymidylate synthase, which catalyzes the rate-limiting step in deoxythymidine triphosphate (dTTP) biosynthesis, thereby inhibiting DNA replication [74]. Fluoropyrimidines have a narrow therapeutic window and dose-adjustments based on therapeutic drug monitoring (TDM) resulted in increased response-rate and decreased toxicity [75].…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…In fact, tumor genetics has not been a successful way to find patients likely to respond to chemotherapies that target nucleotide metabolism, and giving these drugs based on tissue-of-origin has been the standard practice for decades (36). Some newer agents targeting metabolism also act on cancers in a way that is agnostic to cancer genotypes (10).…”

TAS-102: A Novel Antimetabolite for the 21st Century

“…It specifically inhibits thymidylate synthase (TS), an enzyme that plays a central role in DNA synthesis [8]. TS catalyzes a rate-limiting step in pyrimidine production and is crucial for cellular production of deoxythymidine triphosphate (dTTP).…”

“…Tegafur (or ftorafur) is an oral prodrug of 5FU, which is metabolized in the liver by CYP450 to 5FU [14]. It was synthesized more than 30 years ago and is now used in combination with other compounds that improve its bioavailability and toxicity profile [8]. UFT consists of a combination of tegafur and uracil, which is a substrate for DPD, an enzyme that degrades 5FU.…”