A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor.
Therapeutic successes following treatment of murine tumors with tumor necrosis factor-alpha (TNF) have not been easily applied to clinical oncology because the concentrations of TNF required in humans induces systemic toxicity. This has led us to identify mediators which could sensitize tumors to the effects of TNF, permitting administration of lower doses and possible realization of the therapeutic potential of this cytokine. Our study reports the ability of a novel cytokine, endothelial-monocyte-activating polypeptide II (EMAP II), to sensitize initially resistant murine and human tumors to TNF-induced regression employing a murine model. Recombinant (r) EMAP II was purified from Escherichia coli transformed with a plasmid expressing mature EMAP II. The B16 melanoma, raised in C57BL/6 mice, or a human fibrosarcoma (HT-1080), grown in immunocompromised mice, was injected intratumorally with either vehicle or rEMAP II/heat-treated EMAP II (50-100 micrograms) followed by systemic TNF/heat-treated TNF (5 micrograms) and assessed for tumor volume, hemorrhage, and histologic appearance. Both the B16 melanoma and the HT-1080 human fibrosarcoma underwent thrombohemorrhagic and acute inflammatory changes concomitant with regression or significantly slowed growth after administration of intratumor EMAP II followed by systemic TNF. Omission or inactivation of either cytokine abrogated this effect. These results demonstrate that local treatment of certain tumors with EMAP II results in enhanced susceptibility to TNF-mediated induction of thrombohemorrhage and regression.
Marvin
M R
MR
Department of Surgery, Columbia University, College of Physicians and Surgeons, New York 10032, USA.
Libutti
S K
SK
Kayton
M
M
Kao
J
J
Hayward
J
J
Grikscheit
T
T
Fan
Y
Y
Brett
J
J
Weinberg
A
A
Nowygrod
R
R
LoGerfo
P
P
Feind
C
C
Hansen
K S
KS
Schwartz
M
M
Stern
D
D
Chabot
J
J
D000818:Animals; D003001:Cloning, Molecular; D016207:Cytokines; D019008:Drug Resistance, Neoplasm; D004926:Escherichia coli; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D007249:Inflammation; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000627:therapeutic use*; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use* / Q000633:toxicity
D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1