Antipurines

Purine analogues are widely used to treat leukaemias and as immuno-suppressives (azathioprine) and anti-virals (acyclovir, gancyclovir).

6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) both inhibit de novo purine synthesis and their nucleotide products are incorporated into DNA. HGPRT produces monophosphates, which inhibit early stages of purine synthesis, and then convert into tri-phosphates which are incorporated into DNA, causing strand breaks. There are synergistic effects with MTX, due to PRPP build-up, facilitating phosphorylation by HGPRT. Resistance develops due to HGPRT deficiency and reduced substrate affinity. Variable oral bioavailability may contribute to some treatment failures in childhood ALL.

Both drugs have a short half-life and are primarily metabolized— the important difference is that 6-MP is a substrate for xanthine oxidase, and dose alterations are necessary when co-administered with allopurinol. There is poor CSF penetration, but otherwise these agents are widely distributed.

Main toxicity is myelosuppression, but 6-MP can also cause hepato-toxicity. Nausea, vomiting, and mucositis can also occur, more commonly with 6-MP. The commonest indication is haematological malignancy: 6-MP is used for maintenance therapy of ALL, and 6-TG is used for both remission induction and maintenance in AML.

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