How Allopurinol Prevents Tumor Lysis Syndrome
Allopurinol prevents tumor lysis syndrome by inhibiting xanthine oxidase, thus decreasing the formation of uric acid from purine nucleic acid catabolism. 1 This mechanism is crucial in preventing hyperuricemia, which is a key component of tumor lysis syndrome.
Mechanism of Action
Allopurinol works through the following mechanisms:
Inhibition of Xanthine Oxidase: Allopurinol blocks the enzyme xanthine oxidase, which is responsible for converting xanthine and hypoxanthine to uric acid in the purine catabolism pathway 1
Prevention of New Uric Acid Formation: By inhibiting this enzymatic conversion, allopurinol prevents the formation of new uric acid, which can precipitate in renal tubules and cause acute kidney injury during tumor lysis 1, 2
Reduction of Hyperuricemia Risk: This action helps prevent the development of hyperuricemia, a major metabolic complication of tumor lysis syndrome 1
Clinical Application
Allopurinol is administered according to specific protocols:
Dosing: 100 mg/m²/dose every 8 hours (10 mg/kg/day divided every 8 hours) orally (maximum 800 mg/day) or 200-400 mg/m²/day in 1-3 divided doses intravenously (maximum 600 mg/day) 1
Timing: Treatment typically starts 1-2 days before chemotherapy initiation and continues for 3-7 days afterward, based on ongoing TLS risk 1
Renal Adjustment: Dose reduction of 50% or more is required in patients with renal failure 1
Limitations of Allopurinol
Despite its effectiveness, allopurinol has several important limitations:
Ineffective Against Pre-existing Uric Acid: Allopurinol only prevents new uric acid formation and cannot reduce uric acid levels that developed before treatment initiation 1
Delayed Effect: It may take several days for reductions in uric acid levels to occur, potentially necessitating delays in cytotoxic therapy 1
Xanthine Accumulation: Allopurinol causes an increase in xanthine and hypoxanthine levels, which can lead to xanthine crystal deposition in renal tubules and acute obstructive uropathy 1, 3
Drug Interactions: Allopurinol reduces the clearance of purine-based chemotherapeutic agents (e.g., 6-mercaptopurine, azathioprine), requiring dose reductions of 65-75% when used concomitantly 1
Reduced Methotrexate Clearance: Compared to urate oxidase treatment, allopurinol has been associated with reduced clearance of high-dose methotrexate due to decreased renal function 1
Contraindications: Allopurinol is contraindicated with cyclophosphamide and certain cytotoxic agents due to increased bone marrow suppression 1
Hypersensitivity Reactions: Can cause cutaneous rash or fever in some patients 1
When to Use Rasburicase Instead
For certain high-risk patients, rasburicase (recombinant urate oxidase) is preferred over allopurinol:
Pre-existing Hyperuricemia: For patients with uric acid levels >450 μmol/L or 7.5 mg/dL 1
High-Risk Patients: Those with bulky disease, high-grade lymphomas, acute lymphoblastic leukemia, or elevated LDH (>2x upper normal limit) 1
Renal Dysfunction: Patients with pre-existing renal impairment 1, 4
Key Differences Between Allopurinol and Rasburicase
Mechanism: Allopurinol prevents new uric acid formation, while rasburicase actively breaks down existing uric acid to allantoin (5-10 times more soluble) 1, 5
Onset of Action: Rasburicase reduces serum uric acid levels within 4 hours, whereas allopurinol takes days 6, 4
Pre-existing Hyperuricemia: Rasburicase effectively reduces pre-existing elevated uric acid levels, which allopurinol cannot 4
By understanding these mechanisms and limitations, clinicians can appropriately select between allopurinol and rasburicase for TLS prevention based on patient risk factors and clinical presentation.