Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 9; no. 1; pp. 20 - 28
• Main Authors: Yamashita, Yoji, Krauze, Michal T, Kawaguchi, Tomohiro, Noble, Charles O, Drummond, Daryl C, Park, John W, Bankiewicz, Krystof S
• Format: Journal Article
• Language: English
• Published: England 01.01.2007
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cell Line, Tumor; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Drug Delivery Systems; Glioblastoma - drug therapy; Glioblastoma - pathology; Humans; Male; Polyethylene Glycols - administration & dosage; Rats; Rats, Nude; Rats, Sprague-Dawley; Survival Rate; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Topotecan - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1522-8517
• DOI: 10.1215/15228517-2006-016

Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in singleagent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas.