Research Papers:

Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma

Anna Lisa Iorio, Martina da Ros, Lorenzo Genitori, Maurizio Lucchesi, Fabiana Colelli, Giacomo Signorino, Francesco Cardile, Giacomo Laffi, Maurizio de Martino, Claudio Pisano and Iacopo Sardi _

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Oncotarget. 2017; 8:89595-89606. https://doi.org/10.18632/oncotarget.19875

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Anna Lisa Iorio1, Martina da Ros1, Lorenzo Genitori1, Maurizio Lucchesi1, Fabiana Colelli2, Giacomo Signorino2, Francesco Cardile2, Giacomo Laffi3, Maurizio de Martino1, Claudio Pisano2 and Iacopo Sardi1

1Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, Florence, Italy

2BIOGEM Research Institute, Ariano Irpino, Italy

3Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

Correspondence to:

Iacopo Sardi, email: [email protected]

Keywords: temozolomide, glioblastoma, morphine, blood-brain barrier, animal model

Received: November 15, 2016    Accepted: July 13, 2017    Published: August 03, 2017


Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months.

Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ.

The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy.

The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models.

The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB.

In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM.

Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy.

Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments.

In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy.

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