5-Fluorouracil (5-FU) is a typical fluoropyrimidine drug and a representative of this class. Chemically, fluoropyrimidine drugs are defined as drugs where a fluorine atom replaces a hydrogen atom at the 5-position of the pyrimidine ring. The structure of 5-FU derives from uracil, a pyrimidine base naturally found in RNA, which is precisely where the fluorination at the 5-carbon atom occurs. This structural feature led to its name "fluoropyrimidine," and it was the first drug of its kind, introduced by Heidelberger et al. in 1957.

Fluoropyrimidines represent one of the most extensively utilized classes of antimetabolite chemotherapeutic agents in modern oncology, with 5-fluorouracil (5-FU) serving as the prototype molecule first synthesized by Heidelberger et al. in 1957 and subsequently approved by the FDA in 1962. This class of compounds exerts its antineoplastic effects primarily through the inhibition of thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate required for DNA replication. The active metabolite fluorodeoxyuridine monophosphate (FdUMP) forms a stable ternary complex with TS and N⁵,¹⁰-methylenetetrahydrofolate, effectively blocking the methylation of deoxyuridine monophosphate to deoxythymidine monophosphate and thereby inducing S-phase-specific cytotoxicity. Secondary mechanisms include the incorporation of fluorouridine triphosphate (FUTP) into RNA, disrupting normal RNA processing and function, and the incorporation of fluorodeoxyuridine triphosphate (FdUTP) into DNA, leading to DNA damage and apoptotic cell death.

The therapeutic landscape of fluoropyrimidines has evolved substantially from intravenous 5-FU administration to encompass a diverse array of prodrugs and combination formulations designed to optimize pharmacokinetic profiles and enhance tumor selectivity. Capecitabine (CAS No.154361-50-9), an oral prodrug activated through a three-step enzymatic cascade involving carboxylesterase, cytidine deaminase, and thymidine phosphorylase, offers the advantage of preferential conversion to active 5-FU within tumor tissues where thymidine phosphorylase expression is elevated. This tumor-targeted activation mechanism reduces systemic exposure and improves the therapeutic index compared to conventional intravenous 5-FU. Other notable formulations include tegafur-based combinations such as UFT (tegafur plus uracil) and S-1 (tegafur combined with gimeracil, a dihydropyrimidine dehydrogenase inhibitor, and oteracil potassium, which reduces gastrointestinal toxicity), as well as doxifluridine and the investigational agent TAS-102 (trifluridine/tipiracil). These agents collectively form the backbone of chemotherapy regimens for colorectal, gastric, breast, pancreatic, and head and neck malignancies, frequently employed in combination protocols such as FOLFOX (5-FU/leucovorin/oxaliplatin), FOLFIRI (5-FU/leucovorin/irinotecan), and XELOX (capecitabine/oxaliplatin).

Despite their established efficacy, fluoropyrimidines are associated with a spectrum of dose-limiting toxicities that warrant careful clinical management. Gastrointestinal manifestations including mucositis, diarrhea, and nausea represent common adverse effects, alongside myelosuppression characterized by neutropenia and thrombocytopenia. Capecitabine is notably associated with hand-foot syndrome (palmar-plantar erythrodysesthesia), a dose-dependent dermatological toxicity that can significantly impact patient quality of life. Of particular concern is the interindividual variability in drug metabolism attributable to genetic polymorphisms in dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for 5-FU catabolism. DPD deficiency, occurring in approximately 3-5% of the population, can result in life-threatening toxicities including severe neutropenia, mucositis, and neurotoxicity due to excessive drug accumulation. Current guidelines increasingly advocate for prospective DPYD genotyping to guide dose individualization and prevent severe adverse events.

Cardiotoxicity represents a serious yet frequently underappreciated complication of fluoropyrimidine therapy, with reported incidence rates varying dramatically from 1.6% to 68% depending on diagnostic criteria, administration schedules, and patient populations. The European Society of Cardiology estimates the frequency of myocardial ischemia at up to 10%, though symptomatic cardiotoxicity typically occurs in 1-5% of treated patients. Clinical manifestations encompass a broad spectrum including angina pectoris, myocardial infarction, cardiogenic shock, arrhythmias (atrial fibrillation, ventricular tachycardia, heart block), coronary vasospasm, and Takotsubo cardiomyopathy. Notably, cardiotoxic events frequently manifest during initial drug exposure, with a median onset of 12 hours following administration, though delayed presentations up to two days post-infusion have been documented. The pathophysiology of fluoropyrimidine-induced cardiotoxicity is multifactorial, involving coronary vasospasm mediated by endothelial dysfunction and smooth muscle contraction, oxidative stress with reactive oxygen species generation, mitochondrial energy depletion through Krebs cycle inhibition by toxic metabolites such as fluoroacetate, thrombogenic effects on vascular endothelium, and impaired oxygen delivery secondary to erythrocyte membrane alterations.

Risk stratification for cardiotoxicity necessitates comprehensive cardiovascular assessment prior to treatment initiation. Established risk factors include pre-existing coronary artery disease, prior chest wall irradiation, renal insufficiency, concomitant therapy with platinum compounds or bevacizumab, and potentially female sex and specific enzyme polymorphisms. The management of acute cardiotoxicity mandates immediate discontinuation of the offending agent, implementation of standard anti-ischemic therapy with nitrates, beta-blockers, and calcium channel blockers, and appropriate cardiac monitoring. Uridine triacetate has emerged as a specific antidote for 5-FU overdose, competitively inhibiting the incorporation of cytotoxic metabolites into RNA. Rechallenge with fluoropyrimidines following documented cardiotoxicity is generally contraindicated due to high recurrence rates (82-100%) and substantial mortality (approaching 18%); however, if no therapeutic alternatives exist, cautious reintroduction with reduced dosing, prophylactic vasodilator therapy, and continuous cardiac monitoring may be considered. Alternative agents such as raltitrexed, a direct thymidylate synthase inhibitor with distinct cardiovascular safety profiles, or TAS-102 with its DPD-inhibitory component, offer viable options for patients with prior fluoropyrimidine-associated cardiac events.

In conclusion, fluoropyrimidines remain indispensable components of contemporary cancer chemotherapy, with ongoing research focused on refining patient selection through pharmacogenomic profiling, optimizing administration schedules to minimize toxicity, and developing cardioprotective strategies. The integration of multidisciplinary cardio-oncology care is essential to balance therapeutic efficacy with cardiovascular safety in this expanding patient population.