title: The effect of cyclosporin A used alone and in combination with either 2-chlorodeoxyadenosine or fludarabine on normal and chronic myelogenous leukemia progenitors in vitro.
abstract: We evaluated the influence of cyclosporin A (CsA) used alone or together with the new purine nucleoside analogues (PNAs) 2-chlorodeoxyadenosine (2-CdA) and fludarabine (F-ara-A) on the colony growth of normal and chronic myelogenous leukemia (CML) granulocyte-macrophage progenitor cells (CFU-GM) in cultures in vitro. The assay was based on the Iscove's method in our modification. Specimens of bone marrow were collected from 15 patients with CML in the chronic phase and from 10 hematologically normal patients. CsA at the concentrations of 1, 2 and 4 microg/ml was used alone and, at the concentration of 4 microg/ml, was preincubated with mononuclear cells (MNCs) and, after 30 min PNAs were added to the culture medium. Concentrations of 5, 10, and 20 nM 2-CdA and 0.4, 0.8 and 1.6 microM F-ara-A were used. After 14 days of incubation, the colonies were scored under an inverted microscope. We observed that CsA used alone at all three concentrations inhibited the colony growth of CML CFU-GM to a statistically significant degree compared with the control (p < 0.02) and that it did not significantly influence normal colony growth. The IC50 for CsA was 3.9 microg/ml in the case of normal CFU-GM and 2.7 microg/ml in the case of CML CFU-GM. After the use of CsA in combination with either the highest concentrations of 2-CdA or F-ara-A, statistically significant differences compared with CsA used alone were observed (p = 0.008, p = 0.03 for CsA with 2-CdA, and p = 0.0007, p = 0.005 for CsA with F-ara-A, respectively, for normal and CML CFU-GM). However, there were no significant differences between the combinations of drugs and PNAs used alone. In the case of the combination of CsA with the highest concentrations of both PNAs, significant differences in colony growth inhibition between normal and CML CFU-GM were observed (p = 0.002 and p = 0.005, respectively, for 2-CdA and F-ara-A). In conclusion, at the concentrations of the drugs used, a subadditive action was observed either between CsA and 2-CdA or between CsA and F-ara-A.
authors.affiliation: Department of Hematology, Medical University of Lódź, Pabianicka 62, 93-513 Lódź, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Korycka
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017338:Cladribine / Q000494:pharmacology* / Q000627:therapeutic use; D003114:Colony-Forming Units Assay; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008875:Middle Aged; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017338:Cladribine; D016572:Cyclosporine; D014740:Vidarabine; C024352:fludarabine