Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo.
This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.
Bello
L
L
Institute of Neurosurgery, University of Milano, Ospedale Maggiore Policlinico, IRCCS, Milan, Italy. lbello@rics.bwh.harvard.edu
Carrabba
G
G
Giussani
C
C
Lucini
V
V
Cerutti
F
F
Scaglione
F
F
Landré
J
J
Pluderi
M
M
Tomei
G
G
Villani
R
R
Carroll
R S
RS
Black
P M
PM
Bikfalvi
A
A
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005047:Etoposide; D016190:Carboplatin; D020778:Matrix Metalloproteinase 2