Long-term inhibition of glioma growth by systemic administration of human PEX.
OBJECTIVE
The growth of gliomas depends on the balance of factors stimulating or inhibiting angiogenesis, tumor cell invasion and proliferation. The administration of endogenous inhibitors to experimental human gliomas in animal models resulted in a significant inhibition of tumor growth. It is becoming apparent that resistance can develop over time to many types of endogenous inhibitors and seems to be influenced by the tumor type and system of delivery.


METHODS
We recently isolated a potent endogenous inhibitor, called human PEX, from human glioma cells in culture. Human PEX is a potent inhibitor of angiogenesis, tumor and endothelial cell proliferation and migration. In this paper, we investigated the ability of human PEX to sustain inhibition of glioma growth for a prolonged period of time. We initially developed a recombinant form of the inhibitor and showed that this form had similar in vitro and in vivo activities to the natural one. Human PEX was then administered to nude mice intracranial human glioma model, in combination with metronomic chemotherapy, for a period of 185 days, starting 15 days after tumor cells implantation.


RESULTS
Our data showed that the systemic administration of human PEX mantained a very prolonged inhibition of glioma growth (50% survival of animals treated with 2 mg/kg/days was 160 days vs 24 days of the control) and had a synergistic effect with low dose chemotherapy. Histological analysis of tumors, showed that treatment with PEX was associated with a decrease of vascularity, cell proliferation, and increase in apoptosis.


CONCLUSIONS
These data indicate that human PEX controls tumor growth by separate mechanisms. In addition, treatment with PEX produced well delineated tumors, indicating the persistence of a direct anti-invasive effect of the molecule even after a prolonged period of treatment.
Pluderi
M
M
Neurosurgery, Department of Neurological Sciences, University of Milan, Milan, Italy.
Lucini
V
V
Caronzolo
D
D
Pannacci
M
M
Costa
F
F
Carrabba
G
G
Giussani
C
C
Grosso
S
S
Colleoni
F
F
Scaglione
F
F
Villani
R
R
Bikfalvi
A
A
Bello
L
L
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D020778:Matrix Metalloproteinase 2