title: Activation of KATP channels increases anticancer drug delivery to brain tumors and survival.
abstract: Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2/neu over expressing gliomas may work well when combined with temozolomide. Nonetheless, both drugs do not cross the BTB to significantly impact patient survival. Beforehand we showed that potassium channel agonists when intracarotidly administered increased carboplatin and Her-2 antibody delivery in animal glioma models by triggering formation of brain vascular endothelial transcytotic vesicles. In this study, we investigated whether, intravenously administered, ATP-sensitive potassium channel (K(ATP)) activator (minoxidil sulfate; MS) increases temozolomide and Herceptin delivery to brain tumors to induce anti-tumor activity and increase survival in nude mice with Glioblastoma multiforme (GBM) cells. The results clearly demonstrate that when given intravenously temozolomide crosses BTB at a relatively low amount while Herceptin failed to cross the BTB. However, MS co-infusion with [(14)C]-temozolomide or fluorescently labeled-Herceptin resulted in improved and selective drug delivery to brain tumor. We also showed that combination treatment with temozolomide and Herceptin has enhanced anti-tumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with GBM when co-infused with MS. Therefore, brain tumor patients may be benefited when anti-neoplastic agent delivery is increased selectively to the brain tumors using KATP channel agonists.
authors.affiliation: Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Hoskins Center for Biomedical Research, Savannah, Georgia 31404, United States. ningana1@memorialhealth.com
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Ningaraj
authors.forename: Umesh T
authors.initials: UT
authors.lastname: Sankpal
authors.forename: Divya
authors.initials: D
authors.lastname: Khaitan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Meister
authors.forename: Trib
authors.initials: T
authors.lastname: Vats
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000737:chemistry; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D054086:KATP Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008914:Minoxidil / Q000031:analogs & derivatives / Q000494:pharmacology; D015996:Survival Rate; D000077204:Temozolomide; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D054086:KATP Channels; C039516:minoxidil sulfate ester; D008914:Minoxidil; D003606:Dacarbazine; D000068878:Trastuzumab; D000077204:Temozolomide