Da Ros Martina, Iorio Anna Lisa, De Gregorio Veronica, Fantappiè Ornella, Laffi Giacomo, de Martino Maurizio, Pisano Claudio, Genitori Lorenzo, Sardi Iacopo
Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Oncotarget. 2018 Oct 9;9(79):34935-34944. doi: 10.18632/oncotarget.26183.
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 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% vehicle). On the other hand, when combined to TMZ, Aldox caused a significant TVI (P=0.0175 vehicle) and delayed the mortality during the experimental period, although TVI and endpoint survival percentage (+37.5% vehicle) were not significantly different from TMZ alone. Our preliminary data showed that Aldox exerts anti-glioma effects and . It also enhances its antitumor activity when combined with TMZ, resulting in a superior efficacy compared to the single agents, without adverse side effects.
多形性胶质母细胞瘤（GBM）仍然是一种无法治愈的疾病。基于一线替莫唑胺（TMZ）的治疗效果不佳，这凸显了新疗法的必要性。临床前研究中，阿霉素（Dox）的新型前药醛阿霉素（Aldox）已成功针对GBM进行了测试，这促使人们研究其与其他药物联合使用的情况。我们首次在GBM的临床前模型中评估了Aldox与TMZ联合使用的有效性。我们的结果表明，Aldox的抗胶质瘤作用比TMZ更显著，并且它们的联合使用增强了蒽环类药物对TMZ耐药GBM细胞的杀伤作用。此外，与Dox不同，由于P-糖蛋白（P-gp）功能的负调控，Aldox能够在P-gp过表达的细胞中积累。我们还比较了在U87异种移植小鼠模型中，每周给予Aldox（16 mg/kg）单独或与TMZ（0.9 mg/kg，每日注射）联合使用时的疗效和安全性。Aldox治疗诱导了适度的肿瘤体积抑制（TVI）并提高了生存率（相对于赋形剂提高了12.5%）。另一方面，当与TMZ联合使用时，Aldox导致了显著的TVI（与赋形剂相比P = 0.0175），并在实验期间延迟了死亡率，尽管TVI和终点生存率（相对于赋形剂提高了37.5%）与单独使用TMZ时没有显著差异。我们的初步数据表明，Aldox具有抗胶质瘤作用，并且与TMZ联合使用时还增强了其抗肿瘤活性，与单一药物相比疗效更佳，且无不良副作用。
