Abstract
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.
Highlights
IntroductionThere is a need for new approaches that may be able to achieve improved outcomes in Glioblastoma (GBM) patients.despite multimodal approach of radiotherapy plus concurrent and adjuvant Temozolomide (TMZ), the prognosis for patients has not changed significantly for over ten years.A shared issue among these malignancies that affects the efficacy of anticancer therapies involves the Blood-Brain Barrier (BBB); it represents a major hurdle for the delivery of drugs into the brain, contributing to the poor response of brain tumors to chemotherapy.Doxorubicin (Dox) is an effective anti-glioma agent, but its clinical application is primarily limited by inability to cross the BBB [1].At the present, various strategies have been emerged in order to increase the therapeutic use of the drug, including the incorporation in nanoscale carriers as liposomes, polymer and peptide/protein conjugates, polymeric micelles, nanoparticles [2].An attractive new approach is a delivery system that exploits albumin as a drug carrier
A shared issue among these malignancies that affects the efficacy of anticancer therapies involves the Blood-Brain Barrier (BBB); it represents a major hurdle for the delivery of drugs into the brain, contributing to the poor response of brain tumors to chemotherapy
Effect of association of TMZ with Aldox on Glioblastoma Multiforme (GBM) growth and apoptosis in vitro We investigated the responsiveness of three GBM cell lines (U87MG, A172 and T98G) to the killing effect of the Aldox (12 μM) and TMZ (100 μM and 200 μM) exposure and the co-treatment Aldox plus TMZ
Summary
There is a need for new approaches that may be able to achieve improved outcomes in Glioblastoma (GBM) patients.despite multimodal approach of radiotherapy plus concurrent and adjuvant Temozolomide (TMZ), the prognosis for patients has not changed significantly for over ten years.A shared issue among these malignancies that affects the efficacy of anticancer therapies involves the Blood-Brain Barrier (BBB); it represents a major hurdle for the delivery of drugs into the brain, contributing to the poor response of brain tumors to chemotherapy.Doxorubicin (Dox) is an effective anti-glioma agent, but its clinical application is primarily limited by inability to cross the BBB [1].At the present, various strategies have been emerged in order to increase the therapeutic use of the drug, including the incorporation in nanoscale carriers as liposomes, polymer and peptide/protein conjugates, polymeric micelles, nanoparticles [2].An attractive new approach is a delivery system that exploits albumin as a drug carrier. There is a need for new approaches that may be able to achieve improved outcomes in Glioblastoma (GBM) patients. Despite multimodal approach of radiotherapy plus concurrent and adjuvant Temozolomide (TMZ), the prognosis for patients has not changed significantly for over ten years. A shared issue among these malignancies that affects the efficacy of anticancer therapies involves the Blood-Brain Barrier (BBB); it represents a major hurdle for the delivery of drugs into the brain, contributing to the poor response of brain tumors to chemotherapy. Doxorubicin (Dox) is an effective anti-glioma agent, but its clinical application is primarily limited by inability to cross the BBB [1]. An attractive new approach is a delivery system that exploits albumin as a drug carrier
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