Tumor lysis syndrome and hyperuricamia:
What is beyond allopurinol?
 

Tumour lysis syndrome (TLS) refers to spontaneous or treatment induced massive destruction of malignant cells with excessive release of intracellular contents into the blood stream. The syndrome consists of major metabolic disturbance in the form of hyperuricemia (HU), hyperphosphatemia, hyperkalemia and hypocalcaemia. HU may lead to precipitation of uric acid crystals in renal tubules and distal collecting system resulting in acute renal failure.
The standard approach in such cases in vigorous hydration (3 L/m2/day), osmotic diuresis and alkalanization of urine to prevent  uric acid crystalization in the renal tubules. Allopurinol is the only drug currently available in most countries to lower uric acid serum level. It acts by inhibition of xanthine oxidase enzyme and hence it prevents the conversion of xanthines to uric acid. Despite the use of the above measures around 20% of patients with advanced Burkitt’s lymphoma might still require dialysis during induction chemotherapy.
Although Allopurinol successfully blocks the denovo formation of uric acid, yet 2 clinically relevant  metabolic problems are expected: 1^st allopurinol does not degrade pre existing uric acid, 2^nd alloputinol will lead to increase serum level of xanthine. Xanthine buildup  may aggravate renal impairment as it is less soluble than uric acid in alkaline medium. Furthermore alkalinization of urine may also enhance precipitation of phosphate ending up again by renal failure.
Obviously a drug with a direct uricolytic properties is extremely needed in this context to minimize morbidly and mortality  of TLS.
Non-recombinate urate oxidase extracted from Aspergilus flavus has been commercially available as Uricozyme (Sanofi-Synthelabo) in France since 1975 and Italy since 1984. It can be given intramuscularly or intravenously. Urate oxidase degrades uric acid to allantoin, which is 5- to 10-fold more soluble than uric acid. The drug is effective in the prevention and treatment of hyperuicaemia in patients with malignancy and in those who have undergone transplantation and cannot receive allopurinol due to concomitant azathioprine therapy. In fact, urate oxidase reduces uric acid levels more effectively and corrects renal dysfunction more rapidly than allopurinol in patients treated for lymphoid malignancies. However, this preparation was associated with acute hypersensitivity reactions that manifested as bronchospasm and hypoxaemia in as many as 5% of patients. In addition, the production process has a low yield, resulting in a limited supply of the drug. Recently, the recombinant urate oxidase (rasburicase) was developed to overcome those problem associated with the non-recombinant product.
Clinical studies using Rasburicase (Fasurtec) suggest almost 100% efficacy in prevention and treatment of HU and TLS. In a randomized trial, Rasburicase was more effective than Allupurinol. Except for occasional instances of haemolytic anaemia and methemoglobinaemia in patients with G6PD. Rasburicase is well tolerated, with low frequency of mild adverse events. Rasburicase is therefore a very promising advance in the management of HU and TLS.
More recent studies have shown that treatment of established HU and TLS with Fasurtec is cost-saving in children and highly cost-effective in adults.

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