Inhibition of AIDS-associated Kaposi's sarcoma cell growth by DAB389-interleukin 6

AIDS Res Hum Retroviruses. 1994 Aug;10(8):969-75. doi: 10.1089/aid.1994.10.969.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acquired Immunodeficiency Syndrome / complications*
  • Base Sequence
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Diphtheria Toxin / genetics
  • Diphtheria Toxin / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Hematopoietic Stem Cells / drug effects
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / pharmacology*
  • Kinetics
  • Molecular Sequence Data
  • Mutation / physiology
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / analysis
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Sarcoma, Kaposi / complications
  • Sarcoma, Kaposi / metabolism
  • Sarcoma, Kaposi / pathology*
  • Tumor Cells, Cultured

Substances

  • DAB(389)-interleukin 6
  • Diphtheria Toxin
  • Interleukin-6
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins