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Assessment of the therapeutic potential of cytokines, cytotoxic drugs and effector cell populations for the treatment of multiple myeloma using the 5T33 murine myeloma model
Author(s) -
MANNING LINDA S,
CHAMBERLAIN NARELLE L,
LEAHY MICHAEL F,
CORDINGLEY FRANK T
Publication year - 1995
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.1995.50
Subject(s) - melphalan , multiple myeloma , in vivo , cytotoxic t cell , pharmacology , medicine , immunology , in vitro , cytotoxicity , cancer research , biology , biochemistry , microbiology and biotechnology
Summary The therapeutic potential of six cytokines, eight cytotoxic drugs and two effector cell populations for the treatment of multiple myeloma was assessed in vitro using the 5T33 murine myeloma model. The efficacy of combination IFN‐α and melphalan therapy was also evaluated in vitro and in vivo. Of the cytokines tested in vitro using the MTT assay, only IFN‐α demonstrated significant inhibition of myeloma cell growth at non‐toxic concentrations (ED 50 = 1508.3 ± 181.3 U/mL and 2617.9 ± 334.0 U/mL for murine IFN‐α [mIFN‐α] and human IFN‐α hybrid B/D [hlFN‐α B/D], respectively). The ED 50 for the eight cytotoxic drugs tested ranged from 2.3 × 10 −9 to 4.3 × 10 −13 mol/L and all were within the therapeutic range for humans. Combination hIFN‐α B/D and melphalan were found to be additive in their inhibitory effects on myeloma cell growth in vitro and this finding was confirmed in vivo in C57BL/KaLwRij mice bearing disseminated 5T33 myeloma. Control animals demonstrated a median survival duration of 25.3 days whereas hIFN‐α B/D or melphalan treatment alone increased survival to 30.5 and 33.3 days, respectively ( P < 0.001). Combination IFN‐α/melphalan therapy increased median survival duration to 38.5 days ( P < 0.001) which was also significantly greater than that obtained with single agent therapy ( P < 0.01). The murine myeloma cells were found to be resistant to NK cell lysis but susceptible to lysis by LAK cells (49.3 ± 6.3% lysis at an effector to target ratio of 100:1). LAK cell precursors were demonstrable in the bone marrow and spleen of tumour‐bearing animals throughout tumour progression. The results of this study suggest that the use of combination immunotherapy/chemotherapy may be more effective than standard chemotherapy alone for the treatment of multiple myeloma.