Combination treatment of 2-chlorodeoxyadenosine and type I interferon on hairy cell leukemia-like cells: cytotoxic effect and MHC-unrestricted killer cell regulation.
Hairy cell leukemia (HCL) is a lymphoproliferative disorder of B lymphocytes. Interferons (IFNs), especially of the alpha (alpha) subtype, have shown a significant antitumor effect in HCL patients. However, the therapeutic effect of IFN-alpha is still rather limited. The purine analogue 2-chlorodeoxy-adenosine (2-CdA) was reported recently to be an effective agent in the treatment of HCL. In the present study, we find that the HCL cell lines HS-1 and HS-2 as well as Eskol and its IFN-resistant clone (IREs-4) are sensitive to the cytotoxic activity of 2-CdA. Combination treatment of IFN-Con1 and 2-CdA results in a synergistic effect at low doses but an additive inhibitory effect at higher concentrations. IREs-4 cells responded only to 2-CdA treatment. All the HCL cell lines are resistant to natural killer (NK) cell-mediated cytotoxicity (CMC) but are relatively sensitive to IFN-Con1-primed or interleukin-2 (IL-2)-primed NK-CMC activities. No inhibition in killing ability was measured when only the effector cells (NK) were treated with 2-CdA. Pretreatment of the HCL target cells with 2-CdA increases their susceptibility to NK-CMC. Pretreatment with IFN-Con1 can reduce the susceptibility of target cells to NK-CMC in HS-1, HS-2, and Eskol cells but not in the IFN-resistant clone IREs-4. 2-CdA abolished this IFN-induced protection against NK-CMC. Normal fibroblasts only responded to treatment with relatively high doses of 2-CdA, and only a moderate additive cell growth inhibitory effect was seen in combination of 2-CdA with IFN-Con1. Only high doses of 2-CdA increased the susceptibility of fibroblast culture to NK-CMC. Thus, combination of IFN-Con1 and 2-CdA results in an in vitro enhancement of the direct antiproliferative/cytotoxic activity of each treatment alone and increases the efficacy of the NK activity against the HCL cell lines.
Reiter
Z
Z
Division of Morphological Sciences, Faculty of Medicine, Technion, Haifa, Israel.
Tomson
S
S
Ozes
O N
ON
Taylor
M W
MW
D002455:Cell Division / Q000187:drug effects; D017338:Cladribine / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D007943:Leukemia, Hairy Cell / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008285:Major Histocompatibility Complex / Q000276:immunology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D007370:Interferon Type I; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D017338:Cladribine; C050739:interferon alfacon-1