demecolcine and Leukemia--Myeloid--Acute

2-Bromo-2'-deoxyadenosine (BdA) is one of a group of recently synthesised halogenated deoxyadenosine analogues that are relatively resistant to inactivation by adenosine deaminase (ADA). Its activity has been studied in human acute myeloid leukemia (AML) in vitro. In these studies BdA behaved as a cycle-active, phase-active agent that blocked cells at the G1-S transition. It did not exhibit significant cross-resistance with cytosine arabinoside (Ara-C) in either clinical AML samples (from patients who exhibited Ara-C resistance in vivo) or in HL60 in which Ara-C resistance had been induced in vitro. Deoxycytidine kinase levels were not reduced in resistant lines. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase (ADA) inhibitor, with BdA produced a simple additive response without the dramatic synergism reported when it is used with deoxyadenosine. This is consistent with the idea that BdA is a poor substrate for ADA. This group of compounds warrants further investigation to determine their suitability for clinical use, especially in situations where Ara-C resistance is likely to be a problem.

Topics: Cell Line; Cytarabine; Cytidine Deaminase; Demecolcine; Deoxyadenosines; Deoxycytidine Kinase; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Flow Cytometry; Humans; Leukemia, Myeloid, Acute; Tumor Cells, Cultured; Tumor Stem Cell Assay

HL-60 cells were exposed to tritiated thymidine (3HTdR) alone (control group), to cytosine arabinoside followed by 3HTdR or to tritium labelled cytosine arabinoside (3H-AraC) for one hour followed by incubation with colcemide to arrest them during metaphase. Autoradiographic slides were prepared and cell counts were at 1, 24, 48 and 72 h. The studies demonstrated that HL-60 cells exposed to high concentrations of AraC (10 micrograms ml-1) can pass through the S-phase as the G2-phase of the cell cycle and enter mitosis. Despite completing the S-phase, the cells exposed to AraC were severely damaged and had already begun to die.

Topics: Autoradiography; Cell Count; Cell Line; Cytarabine; Demecolcine; DNA Replication; Humans; Interphase; Leukemia, Myeloid, Acute; Mitosis; Thymidine; Time Factors

Topics: Bone Marrow Cells; Cells, Cultured; Chromosomes, Human, 21-22 and Y; Colony-Forming Units Assay; Demecolcine; Erythrocytes; Erythropoietin; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Monocytes