Inhibition of AIDS-associated Kaposi's sarcoma cell growth by DAB389-interleukin 6.
Acquired immune deficiency syndrome-associated Kaposi's sarcoma (AIDS-KS)-derived spindle cells produce and use interleukin 6 (IL-6) among several other cytokines as a growth factor. In this study we show that AIDS-KS cells express approximately 1100 high-affinity IL-6 receptors (IL-6R) per cell with a dissociation constant (Kd) of 110 pM. Furthermore, AIDS-KS cells express the IL-6R alpha subunit, detected as a single 5.0-kb messenger ribonucleic acid species, and the high-affinity converting, signal-transducing IL-6R beta subunit designated as gp130. Similarly, tumor tissue obtained from patients with KS and AIDS expresses IL-6R messenger ribonucleic acid. We have exploited the chimeric fusion toxin DAB389-IL-6, which exerts cellular toxicity only to the cells expressing IL-6R. This chimeric protein was engineered by fusion of a truncated diphtheria toxin structural gene, in which the region encoding the native receptor-binding domain was removed and replaced with the gene encoding IL-6. DAB389-IL-6 inhibited protein synthesis in AIDS-KS-derived spindle cells at very low concentrations (IC50 of 3.4 x 10(-11) M). Similarly, inhibition of cell viability by DAB389-IL-6 was observed at equivalent dose levels (IC50 of 5 x 10(-11)). These effects on protein synthesis and cell viability can be abrogated by recombinant human IL-6, indicating receptor specificity. Thus, DAB389-IL-6 is a potential agent for the treatment of AIDS-associated KS.
Masood
R
R
Department of Internal Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Lunardi-Iskandar
Y
Y
Jean
L F
LF
Murphy
J R
JR
Waters
C
C
Gallo
R C
RC
Gill
P
P
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004167:Diphtheria Toxin / Q000235:genetics / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
C081484:DAB(389)-interleukin 6; D004167:Diphtheria Toxin; D015850:Interleukin-6; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins