Abstract
Therapeutic successes following treatment of murine tumors with tumor necrosis factor-α (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 μg) followed by systemic TNF/heat-treated TNF (5 μg) 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 248-255 |
| Number of pages | 8 |
| Journal | Journal of Surgical Research |
| Volume | 63 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jun 1996 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Surgery
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A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor. / Marvin, Michael R.; Libutti, Steven K.; Kayton, Mark; Kao, Janet; Hayward, Joanne; Grikscheit, Tracy; Fan, Yan; Brett, Jerold; Weinberg, A.; Nowygrod, Roman; Logerfo, Paul; Feind, Carl; Hansen, Kristen S.; Schwarz, Margaret; Stern, David; Chabot, John.
In: Journal of Surgical Research, Vol. 63, No. 1, 06.1996, p. 248-255.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor
AU - Marvin, Michael R.
AU - Libutti, Steven K.
AU - Kayton, Mark
AU - Kao, Janet
AU - Hayward, Joanne
AU - Grikscheit, Tracy
AU - Fan, Yan
AU - Brett, Jerold
AU - Weinberg, A.
AU - Nowygrod, Roman
AU - Logerfo, Paul
AU - Feind, Carl
AU - Hansen, Kristen S.
AU - Schwarz, Margaret
AU - Stern, David
AU - Chabot, John
PY - 1996/6
Y1 - 1996/6
N2 - Therapeutic successes following treatment of murine tumors with tumor necrosis factor-α (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 μg) followed by systemic TNF/heat-treated TNF (5 μg) 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.
AB - Therapeutic successes following treatment of murine tumors with tumor necrosis factor-α (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 μg) followed by systemic TNF/heat-treated TNF (5 μg) 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.
UR - http://www.scopus.com/inward/record.url?scp=0029948526&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029948526&partnerID=8YFLogxK
U2 - 10.1006/jsre.1996.0256
DO - 10.1006/jsre.1996.0256
M3 - Article
C2 - 8661206
AN - SCOPUS:0029948526
VL - 63
SP - 248
EP - 255
JO - Journal of Surgical Research
JF - Journal of Surgical Research
SN - 0022-4804
IS - 1
ER -