Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy

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 CC, cells was also shown. In vivo, rats with 100% HSV-tk(+) or 100% HSV-tk(+) intracerebral C.6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 mu g/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 [H-3] 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.