Interleukin-1 alpha increases the preferential cytotoxicity of an interleukin-2-diphtheria toxin fusion protein against neoplastic lymphocytes from patients with the Sezary syndrome compared to normal lymphocytes.
DAB389IL-2 is a recombinant fusion toxin composed of the diphtheria A chain and a protion of the translocating region of the diphtheria B chain, replacing the receptor binding domain with human IL-2. DAB389IL-2 can be safely administered to humans with mycosis fungoides (MF) or Sezary syndrome (SS), and antineoplastic effects occur. This agent binds optimally to the high-affinity IL-2R. The decreased efficiency of uptake by neoplastic cells which do not express the high-affinity IL-2R represents a potential limitation. Treatment of the HUT-78 cutaneous T-cell lymphoma with IL-1 alpha preceding exposure to DAB389IL-2 overcame their resistance to the toxin, IL-1 alpha inducing high-affinity IL-2R expression. Similarly, pretreatment with IL-1 alpha of SS patient lymphocytes demonstrated increased cytotoxicity compared to treatment with the fusion toxin alone. Normal lymphocytes and monocytes were not sensitive to DAB389IL-2 when pretreated with IL-1 alpha, suggesting a differential sensitivity which may be exploited clinically in the treatment of lymphomas.
Salard
D
D
Department of Molecular Pharmacology and Biological Chemistry, Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Kuzel
T M
TM
Samuelson
E
E
Rosen
S
S
Bakouche
O
O
D002460:Cell Line; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects*; D009182:Mycosis Fungoides / Q000097:blood* / Q000188:drug therapy*; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012751:Sezary Syndrome / Q000097:blood* / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000187:drug effects
D004167:Diphtheria Toxin; D007375:Interleukin-1; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins