In the treatment of leukemia there is a long history of drug discovery by chance and serendipity, and hopefully this will continue. Nevertheless, better understanding of the molecular basis of MDS will lead to more targeted drug approaches. The best example of this approach in hematology is the treatment of chronic myeloid leukemia (CML) with imatinib. As noted above, there is spin-off for MDS in the treatment of the t(5;12) with the same drug (imatinib), although targeting a different tyrosine kinase. The commonest abnormalities in MDS are the RAS point mutations and hypermethylation of p15, and both are under scrutiny from the pharmaceutical companies. Farnesyltransferase inhibitors target multiple pathways, including the RAS pathways. In phase I trials of the farnesyltransferase inhibitor Zarnestra, clinical responses were shown in approximately 30% of patients with high-risk leukemia or MDS.

Low-dose 5-aza-2'deoxycytidine (DAC), a DNA hypo-methylating agent, has been used for the treatment of MDS. A phase II study shows that DAC therapy was effective in half of the studied patients with high-risk MDS and was especially active in the patients with the worst prognosis. Subsequently it was demonstrated that frequent, selective p15 hypermeth-ylation was reversed in responding MDS patients after treatment with a methylation inhibitor. Of course, the methylation status of many genes will be affected by DAC treatment and much more work is needed to resolve the complicated biological issues surrounding this treatment.

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