Aldoxorubicin and Temozolomide combination in a xenograft mice model of human glioblastoma
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Martina Da Ros1, Anna Lisa Iorio1, Veronica De Gregorio1, Ornella Fantappiè2, Giacomo Laffi2, Maurizio de Martino1, Claudio Pisano3, Lorenzo Genitori1 and Iacopo Sardi1
1Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, Florence, Italy
2Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
3BIOGEM Research Institute, Ariano Irpino, Italy
Iacopo Sardi, email: [email protected]
Keywords: aldoxorubicin; temozolomide; glioblastoma; malignant glioma; xenograft model
Received: March 15, 2018 Accepted: September 15, 2018 Published: October 09, 2018
Glioblastoma Multiforme (GBM) is still an incurable disease. The front-line Temozolomide (TMZ)-based therapy suffers from poor efficacy, underlining the need of new therapies.
Preclinically, Aldoxorubicin (Aldox), a novel prodrug of Doxorubicin (Dox), has been successfully tested against GBM, encouraging the study of its association with other agents.
For the first time, we evaluated the effectiveness of Aldox combined to TMZ in preclinical models of GBM.
Our in vitro results demonstrated that the anti–glioma effect of Aldox was more marked than TMZ and their combination increased the killing effect of the anthracycline in TMZ-resistant GBM cells. Moreover, unlike Dox, Aldox was able to accumulate in P-glycoprotein (P-gp)-overexpressed cells due to a negative regulation of the P-gp function.
We also compared efficacy and safety of weekly administrations of Aldox (16 mg/kg), with or without TMZ (0.9 mg/kg, daily injections), in the U87 xenograft mouse model.
Aldox therapy induced a moderate tumor volume inhibition (TVI) and an increased survival rate (+12.5% vs vehicle). On the other hand, when combined to TMZ, Aldox caused a significant TVI (P=0.0175 vs vehicle) and delayed the mortality during the experimental period, although TVI and endpoint survival percentage (+37.5% vs vehicle) were not significantly different from TMZ alone.
Our preliminary data showed that Aldox exerts anti–glioma effects in vitro and in vivo. It also enhances its antitumor activity when combined with TMZ, resulting in a superior efficacy compared to the single agents, without adverse side effects.
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