5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine), an epigenetic drug that inhibits DNA methylation, is currently used to treat myelodysplastic syndrome (MDS), and is under investigation for treating acute myeloid leukemia (AML) and other malignancies. 5-AZA-CdR can reactivate tumor suppressor genes silenced by aberrant DNA methylation, a frequent event in all types of cancer. Because this epigenetic change is reversible, it is a good target for 5-AZA-CdR therapy. We have reviewed the preclinical data of 5-AZA-CdR to analyze the concentrations and exposure times required to eradicate cancer stem cells. We analyzed the dose-schedules used in animal models that show potent antineoplastic activity of 5-AZA-CdR. We attempted to correlate the preclinical data with the responses obtained in clinical trials of 5-AZA-CdR in patients with cancer. The pharmacokinetics and drug distribution of 5-AZA-CdR are key parameters because adequate therapeutic drug levels are required to eliminate cancer stem cells in all anatomic compartments. The plasma half-life of 5-AZA-CdR in humans is approximately 20 minutes due to the high levels in the liver of cytidine deaminase, the enzyme that inactivates this analogue. This provides a rationale to use an inhibitor of cytidine deaminase in combination with 5-AZA-CdR. Low-dose 5-AZA-CdR is effective for MDS and AML and can induce complete remissions (CR). However, maintenance of CR with low-dose 5-AZA-CdR is difficult. Based on analyses of preclinical and clinical data, low dose 5-AZA-CdR has the potential to be an effective form of therapy in some patients with cancer. For patients who do not respond to low dose therapy we recommend dose-intensive treatment with 5-AZA-CdR. Patients who are candidates for intensive dose 5-AZA-CdR should have a good bone marrow status so as to permit adequate recovery from myelosuppression, the major toxicity of 5-AZA-CdR. Solid tumors are also interesting targets for therapy with 5-AZA-CdR. Both low dose and intensive therapy with 5-AZA-CdR can reduce the proliferative potential of tumor stem cells in animal models. We propose novel dose schedules of 5-AZA-CdR for investigation in patients with cancer. The full chemotherapeutic potential of 5-AZA-CdR to treat cancer merits further clinical investigation and can only be realized when its optimal dose-schedule is determined.

5-Aza-2'-deoxycytidine (5-AZA-CdR, Decitabine) is a nucleoside analog and an active drug for the therapy of acute leukemia. The incorporation of 5-AZA-CdR into DNA blocks DNA methylation and can result in the activation of specific genes, such as tumor suppressor genes. This novel mechanism of action of 5-AZA-CdR stimulated our interest in its potential for cancer therapy in patients with lung cancer. Using a colony assay we observed that 5-AZA-CdR showed a potent antineoplastic effect against two human lung carcinoma cell lines. The objective of this preliminary phase I-II study was to evaluate the toxicity and clinical efficacy of 5-AZA-CdR in patients with stage IV non-small cell lung carcinoma. There were 15 patients that entered the clinical study. For nine assessable patients that received 5-AZA-CdR by a single 8 h i.v. infusion of 200-660 mg/m2 for one or more cycles, the median survival duration was 6.7 months, with three patients surviving more than 15 months. The steady-state plasma concentration of 5-AZA-CdR during the infusion was estimated in some patients and was in the same range that produced activation of a tumor suppressor gene in human lung tumor cell lines as reported by other investigators. The major side effect of 5-AZA-CdR was hematopoietic toxicity which required a 5-6 week recovery period before the next cycle of therapy. This study suggests that 5-AZA-CdR may have some clinical activity against metastatic lung carcinoma using this type of dose schedule.