Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia.

5-Aza-2'-deoxycytidine (5-Aza-CdR; Decitabine) is an active antineoplastic agent in patients with leukemia. Since 5-Aza-CdR is an S phase specific agent and has a short plasma half-life, its antileukemic activity is dose schedule-dependent. Leukemia patients who are candidates for 5-Aza-CdR therapy following relapse after therapy with cytosine arabinoside are at greater risk for the problem of drug resistance since these cytosine nucleoside analogues are metabolized by the same enzymes. Due to its unique mechanism of action of demethylating DNA, 5-Aza-CdR has the potential to activate tumor (growth) suppressor and differentiation genes that have been accidentally silenced by DNA methylation in leukemic cells. All these factors should be taken into account in the design of the optimal dose schedule of this analogue. The optimal dose schedule of 5-Aza-CdR should be based on the kinetic parameters of deoxycytidine kinase, its pharmacokinetics, its effects on DNA methylation and the cell cycle parameters of the leukemic cells and the normal hematopoietic stem cells. Since granulocytopenia is the major toxic effect produced by 5-Aza-CdR, the use of hematopoietic growth factors to shorten the duration of leukopenia should be investigated. Another approach which we are investigating is to use the methods of gene therapy to insert the cytidine deaminase gene into normal hematopoietic progenitor cells so as to make them drug resistant to 5-Aza-CdR. The use of other agents that can induce the differentiation of leukemic cells in combination with 5-Aza-CdR may have the potential to increase the clinical effectiveness of this analogue for the therapy of leukemia.