Combinatorial administration of molecules that simultaneously inhibit angiogenesis and invasion leads to increased therapeutic efficacy in mouse models of malignant glioma.
OBJECTIVE
We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth.


METHODS
We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR).


RESULTS
When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined.


CONCLUSIONS
This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.
Bello
Lorenzo
L
Neurosurgery, Department of Neurological Sciences, University of Milano, Ospedale Maggiore di Milano, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy. lorenzo.bello@unimi.it
Lucini
Valeria
V
Costa
Francesco
F
Pluderi
Mauro
M
Giussani
Carlo
C
Acerbi
Francesco
F
Carrabba
Giorgio
G
Pannacci
Marilou
M
Caronzolo
Dario
D
Grosso
Silvia
S
Shinkaruk
Svetlana
S
Colleoni
Federica
F
Canron
Xavier
X
Tomei
Giustino
G
Deleris
Gerard
G
Bikfalvi
Andreas
A
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D009389:Neovascularization, Pathologic; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010456:Peptides, Cyclic / Q000096:biosynthesis; D010978:Platelet Factor 4 / Q000096:biosynthesis; D011506:Proteins / Q000378:metabolism; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors
D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007797:Laminin; D010456:Peptides, Cyclic; D011506:Proteins; D011509:Proteoglycans; D011994:Recombinant Proteins; C478485:cyclo-VEGI; C059485:matrigel; D010978:Platelet Factor 4; D003094:Collagen; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C506232:Phex protein, mouse