In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus

Tomotsugu Ichikawa, Takashi Tamiya, Yoshiaki Adachi, Yasuhiro Ono, Kengo Matsumoto, Tomohisa Furuta, Yoko Yoshida, Hirofumi Hamada, Takashi Ohmoto

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

We evaluated the therapeutic efficacy and neurotoxicity of adenovirus- mediated transduction of the cytosine deaminase (CD) gene and 5- fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1 - weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalCancer Gene Therapy
Volume7
Issue number1
DOIs
Publication statusPublished - 2000

Keywords

  • Adenovirus vector
  • Malignant glioma
  • Neurotoxicity
  • Suicide gene therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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