Effect of cyclosporin A used alone and in combination with either 2-chlorodeoxyadenosine or fludarabine on normal and chronic myelogenous leukemia progenitors in vitro
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We evaluated the influence of cyclosporin A (CsA) used alone or together with 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 method described by Iscove et al. 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 mug/ml was used alone and at the concentration of 4 mug/ml it was preincubated with MNCs and after 30 minutes PNAs were added to the culture medium. 2-CdA at the concentrations of 5, 10, 20 nM and 0.4, 0.8, 1.6 muM of F-ara-A were used. After 14 days of incubation the colonies were scored under inverted microscope. We observed that CsA used alone at all three concentrations in a statistically significant degree inhibited the colony growth of CML CFU-GM, as compared to the control (p<0.02) and it did not significantly influence the normal colony growth. IC50 for CsA was 3.9 mug/ml in case of normal CFU-GM and 2.7 mug/ml in case of CML CFU-GM. After the use of CsA in combination either with the highest concentrations of 2-CdA or F-ara-A, statistically significant differences, as compared to 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 case of the combination of CsA with the highest concentrations of both PNAs significant differences in the 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 used concentrations of the drugs a subadditive action was observed either between CsA and 2-CdA or between CsA and F-ara-A.
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A. Korycka, Department of Hematology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland