Endothelial monocyte activating polypeptide II (EMAP II) enhances the effect of TNF on tumor-associated vasculature.
Endothelial monocyte activating polypeptide II (EMAP II) was initially identified as a factor that may modulate the interaction of tumor necrosis factor (TNF) with tumor vascular endothelium. Since the toxicity of TNF has continued to hamper its clinical use in cancer patients, investigators have developed a renewed interest in modulators such as EMAP II. Over a period of 25 years, investigations into the mechanism of antitumor action of TNF have yielded important observations concerning the role of the microvasculature as the target for TNF's activity. EMAP II was identified as an endothelial response mediator secreted by a highly TNF-sensitive tumor line, the Meth A fibrosarcoma. When used to treat tumors, either by systemic administration of recombinant protein or by gene transfer, EMAP II upregulates cellular receptors for TNF on endothelial cells and confers TNF sensitivity to tumors previously believed to be TNF-resistant. Potential mechanisms for EMAP II's selective effects on endothelial cells have been described. These include induction of endothelial cell apoptosis and upregulation of TNF receptor I (TNFR1). Other recent investigations have posited various physiological roles for EMAP II, ranging from the mediation of inflammation to the vascular remodeling that occurs during normal embryogenesis. EMAP II has generated interest as a modulator of TNF response for isolated whole-organ, isolated limb, or systemic perfusion. By enhancing the tumor vasculature response to TNF, EMAP II may enable lower, non-toxic doses of TNF to be used to clinical advantage.
Kayton
M L
ML
Surgical Metabolism Section, Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA. KaytonM@pop.nci.nih.gov
Libutti
S K
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines; D004357:Drug Synergism; D006801:Humans; D009363:Neoplasm Proteins / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000098:blood supply*; D016601:RNA-Binding Proteins / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1