title: Morphine modulates doxorubicin uptake and improves efficacy of chemotherapy in an intracranial xenograft model of human glioblastoma.
abstract: Morphine may alter the permeability of Blood-Brain Barrier (BBB), enhancing the access of molecules normally unable to cross it, as Doxorubicin (Dox). In addition, morphine seems to mediate the uptake of Dox into the brain by its reduced efflux mediated by P-glycoprotein (P-gp). We evaluated the antitumor efficacy of Dox plus morphine treatment by an orthotopic glioblastoma xenograft model. Foxn1 mice were injected with U87MG-luc cells in the left lobe of the brain and treated with Dox (5 mg/kg and 2.5 mg/kg, weekly) with or without morphine pretreatment (10 mg/kg, weekly). Bioluminescence imaging (BLI) was used to monitoring tumor growth and response to therapy. Additionally, we investigated the role of morphine on the uptake of Dox by MDCKII cells transfected with human MDR1 gene encoding for P-gp. The data demonstrate that only Dox 5 mg/kg determined a significant tumor regression while the lower dose (2.5 mg/kg) was not effective. However, if combined with morphine, the group treated with Dox 2.5 mg/kg showed a decreasing tumor growth. The average BLI for Dox 2.5 mg/kg plus morphine was 5 fold lower than Dox 2.5 mg/kg alone (P=0.0053) and 8 fold lower than vehicle (P=0.0004). Additionally, Dox increased in MDCKII-P-gp transfected cells only in the presence of morphine with a significantly higher level comparing control group (3.84) vs Dox plus morphine group (12.29, P<0.05). Our results indicate that Dox alone and in combination with morphine appear to be effective in controlling the growth of glioblastoma in a xenograft mouse model.
authors.affiliation: Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital Florence, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: da Ros
authors.affiliation: Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital Florence, Italy.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Iorio
authors.affiliation: BIOGEM Research Institute Ariano Irpino, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Consolante
authors.affiliation: BIOGEM Research Institute Ariano Irpino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cardile
authors.affiliation: Department of Experimental, Clinical and Biomedical Sciences, Center of Excellence, DeNothe, University of Florence Florence, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Muratori
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence Florence, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Fantappiè
authors.affiliation: Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital Florence, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Lucchesi
authors.affiliation: Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital Florence, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Guidi
authors.affiliation: BIOGEM Research Institute Ariano Irpino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.affiliation: Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital Florence, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Sardi
keywords: Glioblastoma; P-glycoprotein; blood-brain barrier; doxorubicin; morphine