title: Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.
abstract: Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.
authors.affiliation: Department of Neurological Surgery, Childrens Hospital of Los Angeles, The University of Southern California School of Medicine, 90033, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: LeMay
authors.forename: M
authors.initials: M
authors.lastname: Kittaka
authors.forename: E M
authors.initials: EM
authors.lastname: Gordon
authors.forename: B
authors.initials: B
authors.lastname: Gray
authors.forename: M F
authors.initials: MF
authors.lastname: Stins
authors.forename: J G
authors.initials: JG
authors.lastname: McComb
authors.forename: S
authors.initials: S
authors.lastname: Jovanovic
authors.forename: P
authors.initials: P
authors.lastname: Tabrizi
authors.forename: M H
authors.initials: MH
authors.lastname: Weiss
authors.forename: R
authors.initials: R
authors.lastname: Bartus
authors.forename: W F
authors.initials: WF
authors.lastname: Anderson
authors.forename: B V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D005910:Glioma / Q000628:therapy*; D007262:Infusions, Intravenous; D051379:Mice; D009374:Neoplasms, Experimental; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000998:Antiviral Agents; C089876:RMP 7; D013937:Thymidine Kinase; D015774:Ganciclovir; D001920:Bradykinin