Inhibition of AIDS-associated Kaposi's sarcoma cell growth by DAB389-interleukin 6.
AIDS Res Hum Retroviruses
; 10(8): 969-75, 1994 Aug.
Article
em En
| MEDLINE
| ID: mdl-7811548
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Kaposi
/
Síndrome da Imunodeficiência Adquirida
/
Interleucina-6
/
Toxina Diftérica
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
1994
Tipo de documento:
Article