Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

Faith H. Barnett, Nikolai G. Rainov, Keiro Ikeda, Deborah E. Schuback, Peter Elliott, Christof M. Kramm, Maureen Chase, Nazer H. Qureshi, Griffith Harsh IV, E. Antonio Chiocca, Xandra O. Breakefield

Research output: Contribution to journalArticlepeer-review

Abstract

RMP-7, a bradykinin analog, has been shown to selectively open the blood-tumor barrier for the delivery of chemotherapeutic drugs to brain tumors. In contrast to bradykinin, RMP-7 has no hypotensive effects and has been approved for human use. This study was initiated to determine whether RMP-7 would open the blood-tumor barrier to virus vectors encoding tumor-killing genes in an experimental model. The herpes virus vector used, hrR3, which encodes virus thymidine kinase gene and the lacZ reporter gene, is defective in a gene encoding ribonucleotide reductase, replicates selectively in dividing tumor cells and not in postmitotic neural cells. It was determined that an optimum dose of RMP-7 (1.5-3.0 Mg/kg over 10-15 minutes) enhanced viral delivery to brain tumors in rats bearing intracranial 9 L gliosarcomas when infused through the carotid artery immediately prior to virus vector application. Maximum expression of the lacZ reporter gene occurred at 3 days after intracarotid infusion. By 8 days, transgene expression was largely confined to tumor foci away from the main tumor mass. Viral delivery was essentially specific to tumor cells, with little transgene expression elsewhere in the brain. Minimal uptake and pathology was noted in the kidney, spleen, and liver. These findings indicate that intracarotid delivery of RMP-7 can augment the selective delivery of virus vectors to brain tumors in an experimental rat model, with the potential for application to human brain tumors.

Original languageEnglish (US)
Pages (from-to)14-20
Number of pages7
JournalCancer Gene Therapy
Volume6
Issue number1
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Blood-brain barrier
  • Blood-tumor barrier
  • Carotid artery
  • Gene therapy
  • Herpes simplex virus type I
  • Intra-arterial application

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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