Leukeran
Leukeran
Generic Name
Leukeran
Brand Names
for *5‑fluorouracil*, 5‑FU) is a first‑generation antimetabolite chemotherapy agent that interferes with DNA/RNA synthesis. It is widely used in solid‑tumor oncology and, in combination protocols, in certain acute leukemias.
Mechanism
- Metabolite formation: 5‑FU is converted intracellularly to 5‑fluoro‑deoxyuridine monophosphate (FdUMP).
- Thymidylate synthase inhibition: FdUMP forms a covalent ternary complex with thymidylate synthase (TS) and 5,10‑methylene‑tetrahydrofolate, blocking the conversion of dUMP to dTMP.
- DNA/RNA synthesis interruption: Reduced dTMP leads to “thymineless catastrophe”, impaired DNA replication, and increased incorporation of 5‑FU into RNA, disrupting RNA processing and ribosomal function.
- Rapid cell death: Highly proliferative cells (tumor, hematopoietic progenitors) are most affected.
Pharmacokinetics
| Parameter | Approximate value |
| Absorption | Oral poorly absorbed (~25%); IV formulation guarantees 100% bioavailability. |
| Distribution | 60–70 % bound to plasma proteins; distributes widely, crosses placenta and CSF (especially IV). |
| Metabolism | Primary hepatic via dihydropyrimidine dehydrogenase (DPD) → inactive dihydrouracil; minor CYP1A2/1A3 involvement. |
| Elimination | Renal excretion of metabolites; clearance ≈ 1–2 L h⁻¹. |
| Half‑life | 20–30 min IV bolus; prolonged with slow infusion; overall apparent half‑life ~30 min due to rapid metabolism. |
| Dose‑adjustment | Dependent on DPD activity, renal/hepatic function; routine monitoring of plasma 5‑FU levels is not standard but recommended in high‑dose protocols. |
Indications
- Solid‑tumor malignancies (standard of care or part of combination regimens)
- Colorectal carcinoma (adjuvant/adjuvant)
- Breast carcinoma
- Head and Neck squamous cell carcinoma (HNSCC)
- Esophageal, gastric, and pancreatic adenocarcinomas
- Bladder carcinoma
- Hematologic malignancies (as part of combination therapy)
- Acute myeloid leukemia (AML) – FLT3‑positive regimens
- Non‑Hodgkin lymphoma (in selected salvage protocols)
- Intrathecal therapy for CNS leukemia (rare, used in specific protocols)
- Experimental protocols in research settings (e.g., immunotherapy combinations)
Contraindications
- Absolute contraindication: Severe hepatic impairment (AST/ALT > 5× ULN), severe renal dysfunction (CrCl < 30 mL min⁻¹), pregnancy (Fetus‑placenta barrier) – high teratogenic and embryotoxic risk.
- Relative contraindication:
- DPD deficiency (known or suspected) → life‑threatening toxicity; pre‑therapy screening advised.
- Myelosuppression (ANC < 1.5 × 10⁹ L⁻¹, platelets < 75 × 10⁹ L⁻¹).
- Uncontrolled malnutrition or electrolyte disturbances.
- Warnings:
- Hepatotoxicity, mucositis, myelosuppression.
- Hand‑foot syndrome (palmar‑plantar erythrodysesthesia).
- Neurotoxicity (peripheral neuropathy with extended infusions).
- Severe hypersensitivity reactions (rare).
Dosing
- Standard IV infusion: 5‑FU 2400 mg/m² over 48 h (continuous) is a typical regimen in colorectal cancer (FOLFOX/FOLFIRI).
- Intermittent bolus: 5‑FU 500 mg/m² IV over 2 min, given thrice weekly; combined with leucovorin (LV) 20 mg/m².
- Intrathecal: 15–20 mg 5‑FU dissolved in 2 mL saline, injected once weekly (protocol‑dependent).
- Combination with Leucovorin: Enhances formation of active FdUMP–TS complex; dosing is 20–25 mg/m² with 5‑FU.
- DPD‑screening: Patients with partial DPD deficiency may require reduced dosing (20–30 % ↓) or alternative agents.
Adverse Effects
| System | Common (≥ 10 %) | Serious (< 10 %) |
| Hematologic | Leukopenia, thrombocytopenia, anemia | Profound neutropenia (ANC < 0.5 × 10⁹ L⁻¹) → septic complications |
| Gastro‑intestinal | Nausea, vomiting (≤ 50 %), mucositis, diarrhea | Life‑threatening dehydration, perforation |
| Dermatologic | Hand‑foot syndrome, alopecia | Severe dermatitis |
| Pulmonary | Pneumonitis | Acute respiratory distress syndrome (ARDS) |
| Neurologic | Peripheral neuropathy | Neuropathic pain, seizures (rare) |
| Hepatic | Elevated AST/ALT | Liver failure, hyperbilirubinemia |
| Other | Fever, hypotension (infusion reactions) | Hypersensitivity/anaphylaxis |
Monitoring
- Baseline & periodic labs: CBC with differential, comprehensive metabolic panel (CMP), liver enzymes, renal function.
- Pre‑infusion: Assess for DPD deficiency (genetic or phenotypic testing).
- During infusion: Vital signs, hand‑foot exam, mucosal inspection.
- Post‑therapy: CBC 7‑10 days after each cycle; monitor for delayed neutropenia.
- Special: Dose‑limiting toxicities: grade ≥ 3 diarrhea, mucositis, neutropenia → consider dose adjustment.
Clinical Pearls
- Continuous Infusion Advantage: A 48‑h infusion reduces peak plasma concentrations, lowering mucosal and GI toxicity compared with bolus dosing.
- Leucovorin Synergy: Leucovorin at 20–25 mg/m² potentiates 5‑FU efficacy; omission can reduce therapeutic benefit.
- DPD Testing is Key: Approximately 0.3 % of the U.S. population is completely DPD deficient, and 3–5 % have partial deficiency; pre‑therapy testing (phenylalanine loading or UGT1A1 genotype) prevents catastrophic toxicity.
- Hand‑Foot Syndrome Prevention: Regular moisturization and avoidance of hot water baths help reduce severity.
- Intrathecal Use Caveat: CSF levels of 5‑FU plateau quickly; repeat dosing requires careful scheduling to avoid cumulative neurotoxicity.
- Drug‑Drug Interactions: Steroids and probenecid can prolong 5‑FU half‑life; avoid concurrent strong CYP inhibitors (e.g., ketoconazole) that may alter metabolism.
- Nutrition Matters: Adequate nutrition and caloric intake improve mucosal regeneration and decrease myelosuppression risk.
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• *Reference‑friendly formatting: 5‑fluorouracil (5‑FU) remains a cornerstone of chemotherapy, and Leukeran serves as the prototypical IV formulation. The outlined data align with contemporary oncology guidelines and pharmacology texts (e.g., Goodman & Gilman's, NCCN, ASCO).*