Synergistic antitumor effect of an angiogenesis inhibitor (TNP-470) and tumor necrosis factor in mice.
OBJECTIVE
We investigated the potentiation of combination therapy using tumor necrosis factor (TNF) with TNP-470, a potent angiogenesis inhibitor.


METHODS
We evaluated the antitumor effect in vivo against subcutaneous (s.c.) MC38 mouse colon adenocarcinoma tumors in C57BL/6 mice. The mice were treated with a single bolus injection via the tail vein of 3 or 8 microg rhTNF in 0.5% bovine serum albumin/normal saline (BSA/NS), or with 0.5% BSA/NS alone as a control, with or without TNP-470 pretreatment, given as 30 or 60 mg/kg x 2 days, s.c. DNA synthesis in human umbilical endothelial cells (HUVEC) was assessed by [(3)H]thymidine uptake after incubation with TNF, with or without TNP-470.


RESULTS
The antitumor effect of TNP-470 pretreatment combined with 3 microg recombinant human (rh) TNF injection resulted in an 80% reduction of tumor volume compared with the control. This was significantly better than that induced by 3 microg rhTNF alone (P < 0.005). DNA synthesis in HUVEC was inhibited by TNF with TNP-470 in a dose-dependent manner, but there was no enhanced effect against MC38 in vitro.


CONCLUSIONS
These results suggest that the combination of the angiogenesis inhibitor TNP-470 and TNF might have a synergistic antitumor effect on solid tumors in vivo.
Amikura
Katsumi
K
First Department of Surgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Matsuno
Seiki
S
Egawa
Shinichi
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003510:Cyclohexanes / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011994:Recombinant Proteins; D012717:Sesquiterpenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D014471:Umbilical Veins
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D004273:DNA, Neoplasm; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D000077609:O-(Chloroacetylcarbamoyl)fumagillol