title: Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94103, USA.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Michal T
authors.initials: MT
authors.lastname: Krauze
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Drummond
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D019772:Topotecan / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin