The antileukaemic activity of 5-Aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia

Abstract

In the present study we demonstrate that Aza-dC in combination with Amsacrine has major antileukaemic properties in patients who have not already received extensive Ara-C therapy. Eight out of 11 patients in their first relapse of acute leukaemia achieved complete remission. Cross resistance between Ara-C and Aza-dC was revealed by the lack of antileukaemic activity in five patients with with Ara-C resistant leukaemia. Combination therapy with Aza-dC/Ams-acrine induced a considerable period of a granulocytopenia (28-35 days), while the toxic effect on erythro- and megakaryopoiesis was comparable to that reported for high dose Ara-C/Amsacrine chemotherapy. Remarkable is the long disappearance time for leukaemic blast cells in bone marrow, i.e. 3-5 weeks in some cases. Analysis of cell membrane markers showed a loss of the early differentiation antigens CD34 and CD33 from leukaemic bone marrow cells after 7 days of Aza-dC treatment, which is suggestive of leukaemic cell differentiation. In the small group of patients tested for DNA hypomethylation no association existed between the degree of hypomethylation and clinical response. Non-haematologic side effects were considerable in patients receiving the highest dosages of Aza-dC and consisted of severe, although usually reversible, gastrointestinal and neurological complications. In comparison with Ara-C, Aza-dC causes less nausea and vomiting and is therefore better tolerated.

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

“…Recent reports support the hypothesis on conventional chemotherapy. [5][6][7] In addition, 5-Aza-CdR has that RAR␤ is a tumor suppressor gene. 25,26 shown clinical activity in patients with myelodysplastic synThe role of most tumor suppressor genes in the pathogenesis action is also schedule-dependent.…”

New agents in acute myeloid leukemia and other myeloid disorders

“…19 Several studies have demonstrated the efficacy of decitabine in patients with recurrent or refractory leukemia. 20 The dose-limiting toxicity of decitabine in early Phase I trials was prolonged myelosuppression with minimal extramedullary toxicity. 21,22 In a Phase I study, decitabine was given at a dose of 50 -100 mg/m 2 every 12 hours for 5 days to 130 patients with CML.…”

Avian erythroleukemia: a model for corepressor function in cancer

“…Inhibitors that can a ect corepressor function such as AZAdC and TSA have been successfully used in clinical trials to treat patients with leukemia and myelodysplastic syndromes (Lubbert, 2000;Limonta et al, 1993;Richel et al, 1991). However, details on the molecular mechanisms underlying gene repression and the e ects of AZAdC and TSA on APL blasts are currently scars or missing.…”