Cytarabine (
cytosine arabinoside) is one of the most effective drugs for the treatment of
acute myeloid leukemia. The standard dose of
cytarabine used to treat this
leukemia is 100 mg per square meter. In an attempt to improve the effectiveness of
cytarabine against
acute myeloid leukemia, a high-dose treatment (3,000 mg per square meter) was introduced into
therapy. The side effects of high-dose
cytarabine was a major concern, especially its neurological toxicity. A review of recent clinical trials indicates that this high-dose
cytarabine can be replaced by the intermediate-dose of 1,000 mg per square meter without loss of efficacy and with less toxicity. This is an important step to improve the efficacy of
cytarabine for the treatment of
acute myeloid leukemia. Despite the improvements in the
therapy for this
leukemia, the current overall survival rate for adult patients is less than 30%. To optimize the
cytarabine therapy, it is important to determine how some leukemic stem cells survive treatment. Preclinical data suggest that survival of the leukemic stem cells could be due to the long 12 hour interval between infusions of
cytarabine, which permits some leukemic cells to escape its S phase specific action. Among the other factors that can lead to leukemic cell survival are the high levels in the liver and spleen of
cytidine deaminase, the
enzyme that inactivates
cytarabine and drug resistance due to deficiency in
deoxycytidine kinase, the
enzyme that activates the
prodrug,
cytarabine. Several approaches are proposed in this commentary to overcome these impediments with the goal of increasing the effectiveness of
cytarabine for the treatment of
acute myeloid leukemia.