Antimetabolites and antitumor antibiotics

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5-Fluorouracil (5-FU) Efudix (topical), Fluorouracil Accord (IV)

Pharmacological Group: Antimetabolite, pyrimidine analogue.

Mechanism of Action: 5-FU is a prodrug that requires intracellular conversion to active nucleotides such as 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). FdUMP covalently and competitively inhibits the enzyme thymidylate synthase (TS) by forming a stable ternary complex with the enzyme and the cofactor N5,N10-methylenetetrahydrofolate. This inhibition depletes thymidine triphosphate (dTTP) stores, inhibiting de novo DNA synthesis. Additionally, other metabolites (FUTP) are incorporated directly into cellular RNA, critically interfering with ribosomal RNA processing and protein translation.

Pharmacogenetic Pearl: DPD Deficiency and Leucovorin Rescue

Patients with loss-of-function mutations in the DPYD gene that encodes the DPD enzyme experience dramatically decreased 5-FU clearance. Administration of standard doses in these patients triggers fulminant and life-threatening systemic toxicity (severe pancytopenia, hemorrhagic diarrhea and generalized skin peeling). Synergy Mechanism: Folinic acid (leucovorin) is co-administered in combination therapy with 5-FU to potentiate cytotoxicity: it physically stabilizes the inhibitory ternary complex between FdUMP and thymidylate synthase, prolonging the cellular metabolic blockade.

Infusion Dosage and Contraindications

Continuous Infusion Dosage: mFOLFOX6 Scheme: initial bolus of 400 mg/m² followed by a continuous intravenous infusion of 2400 mg/m² for 46 hours through a portable infusion device.
Absolute Contraindications: Known dihydropyrimidine dehydrogenase (DPD) deficiency; pre-existing severe bone marrow depression; suspected unstable ischemic heart disease. Avoid with warfarin (drastically increases INR).

Pregnancy: Category D (Crosses placental barrier, teratogenic) Breastfeeding: Contraindicated Doxorubicin Adriblastin, Myocet (Liposomal)

Pharmacological Group: Anthracycline antineoplastic antibiotic.

Mechanism of Action: It exerts its cellular cytotoxicity through three integrated and lethal mechanisms: 1. Direct intercalation between base pairs of helical DNA, physically blocking the advance of polymerases. 2. Competitive inhibition and stabilization of the intermediate complex cleaved by the enzyme Topoisomerase II (especially the II-alpha isoform), preventing the sealing of DNA double-strand breaks and blocking mitotic replication. 3. Cytoplasmic formation of highly reactive oxygen free radicals through an iron-mediated reduction reaction; These radicals induce lipid peroxidation of cell membranes and the sarcoplasmic reticulum.

Cardiac Toxicity and Cardioprotection Strategies

Critical Cumulative Dose: The development of toxic dilated cardiomyopathy due to anthracyclines increases exponentially when the cumulative dose of doxorubicin exceeds 450 to 550 mg/m². Above this threshold, the risk of disabling CHF exceeds 20%. Echocardiograms with LVEF calculation are required before starting and periodically.
Prevention and Treatment: The use of pegylated liposomal doxorubicin (Caelyx) formulations dramatically reduces cardiac toxicity. In patients who have reached the limit dose or with previous cardiac risk factors, the cardioprotective antidote dexrazoxane is administered concomitantly, an intracellular iron chelator that minimizes the generation of oxygen radicals in cardiomyocytes without reducing oncological efficacy.

Adult Dosage and Hepatic Adjustment

Conventional Dosage: 60-75 mg/m² IV administered once every 21 days, typically in combination with cyclophosphamide (AC schedule).
Mandatory Hepatic Adjustment: Bilirubin 1.2-3.0 mg/dL: reduce the dose by 50%. Bilirubin >3.0 mg/dL: reduce dose by 75% or discontinue.

Pregnancy: Category D (Crosses placenta, embryonic lethality) Breastfeeding: Contraindicated