TNP-470 fails to block the onset of angiogenesis and early tumor establishment in an intravital minimal disease model.
OBJECTIVE
The angiogenesis inhibitor TNP-470 (AGM-1470) has shown encouraging results in animal models of established tumors. However, results of recent clinical trials using TNP-470 have been disappointing. Since little is known about the effects of TNP-470 at the minimal disease stage, we analyzed the effects of TNP-470 on the early stages of tumor establishment.


METHODS
Twenty thousand green fluorescent protein (GFP)-transfected murine CT-26 (colonic carcinoma) or Panc-02-H0 (pancreatic adenocarcinoma) cells were inoculated in dorsal skin-fold chambers in BALB/c or C57BL6 mice. Tumor area and microvessel density (MVD) were quantified by intravital microscopy (IVM). Body weight was also monitored. Effects were compared with those in a conventional model involving subcutaneous (s.c.) inoculation of 10(6) tumor cells, followed by measurement of tumor volume, endogenous plasma VEGF/endostatin (ELISA) and proliferation/apoptosis/microvessel density (Ki-67/TUNEL/CD-34). TNP-470 was injected s.c. over the 10-day experimental period (30 mg/kg every 2 days [n=6] to 100 mg/kg/day [n=5 dorsal skin-fold chamber model, n=4 s.c. tumor model]).


RESULTS
At 30 mg/kg/every second day neither CT-26 nor PANC-02-H0 tumors were inhibited in neither of the two models. TNP-470 dosage was escalated in CT-26-bearing animals until an antiangiogenic effect could be observed. In the IVM model, only TNP-470 100 mg/kg/day reduced MVD (P=0.006), but failed to block the onset of angiogenesis and tumor area increase. Body weight decreased by 25% (P<0.05). In the subcutaneous tumor model, tumor growth was reduced (P=0.045) but not blocked, while vascular endothelial growth factor (VEGF)/endostatin synthesis and Ki67/TUNEL/CD-34 were not significantly affected.


CONCLUSIONS
While capable of reducing tumor growth in a conventional model, treatment with TNP-470 does not block the onset of angiogenesis and tumor establishment in a model of minimal disease. When used as a single agent TNP-470 does not control minimal tumor disease in experimental colonic carcinoma.
Cernaianu
Grigore
G
Department of Pediatric Surgery, University of Leipzig, 04317, Leipzig, Germany. cerg@medizin.uni-leipzig.de
Frank
Sibylle
S
Erbstösser
Katrin
K
Leonhardt
Sandy
S
Cross
Michael
M
McIvor
Zoe
Z
Scholz
Gabriele
G
Dansranjavin
Temuujin
T
Celik
Ilhan
I
Tannapfel
Andrea
A
Wittekind
Christian
C
Troebs
Ralf-Bodo
RB
Rothe
Karin
K
Bennek
Joachim
J
Hauss
Johann
J
Witzigmann
Helmut
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D003510:Cyclohexanes / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D012717:Sesquiterpenes / Q000494:pharmacology*; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D000077609:O-(Chloroacetylcarbamoyl)fumagillol