title: Suppression of malignant glioma recurrence in a newly developed animal model by endogenous inhibitors.
abstract: Glioma recurrences develop at the borders of the surgical cavity and are the main cause of their poor prognosis. There are no therapeutic advances to reduce the incidence of recurrence or animal models that closely mimic the clinical scenario to evaluate novel therapeutics. This work investigates the efficacy of endogenous inhibitors, in preventing the recurrence of human malignant gliomas, in a newly developed animal model of glioma surgical resection. We developed a nude mice model in which human glioma xenografts were microsurgically removed. After surgery, small islets of tumor cells persisted in the normal brain parenchyma, grew, and formed a recurrence. As inhibitors we used PEX and a fragment of platelet factor 4 (PF-4/CTF), which were administered systemically on a daily basis or in metronomic combination with chemotherapy for 120 days. Treatment was started 1 or 15 days after tumor removal. PEX or PF-4/CTF produced a significant improvement in survival, and delayed the appearance of glioma recurrence. Survival of animals that received daily PEX or PF-4/CTF was similar to that of animals that received metronomic PEX or PF-4/CTF and chemotherapy, respectively. The effect of treatment was dependent on the time at which the treatment was initiated. The highest level of inhibition was observed when the treatment was administered 1 day after surgical resection and when PEX was used as the inhibitor (120 days versus 35 days of the control). Tumors treated with PEX or PF-4/CTF were small and well delineated, with few vessels. Postsurgical administration of PEX or PF-4/CTF significantly reduces the incidence human malignant glioma recurrences for a long period of time.
authors.affiliation: Neurosurgery, Department of Neurological Sciences, University of Milano, Ospedale Maggiore Policlinico, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy. lorenzo.bello@unimi.it
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bello
authors.forename: Carlo
authors.initials: C
authors.lastname: Giussani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carrabba
authors.forename: Mauro
authors.initials: M
authors.lastname: Pluderi
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.forename: Marilou
authors.initials: M
authors.lastname: Pannacci
authors.forename: Dario
authors.initials: D
authors.lastname: Caronzolo
authors.forename: Giustino
authors.initials: G
authors.lastname: Tomei
authors.forename: Roberto
authors.initials: R
authors.lastname: Villani
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Andreas
authors.initials: A
authors.lastname: Bikfalvi
mesh_terms: D000818:Animals; D002455:Cell Division; D004195:Disease Models, Animal; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010978:Platelet Factor 4 / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D012008:Recurrence; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D011994:Recombinant Proteins; D010978:Platelet Factor 4; D020778:Matrix Metalloproteinase 2