Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine

Yoshiaki Adachi, Takashi Tamiya, Tomotsugu Ichikawa, Kin'ya Terada, Yasuhiro Ono, Kengo Matsumoto, Tomohisa Furuta, Hirofumi Hamada, Takashi Ohmoto

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.

Original languageEnglish
Pages (from-to)77-89
Number of pages13
JournalHuman Gene Therapy
Volume11
Issue number1
DOIs
Publication statusPublished - 2000

Fingerprint

uracil phosphoribosyltransferase
Cytosine Deaminase
Flucytosine
Investigational Therapies
Adenoviridae
Brain Neoplasms
Genetic Therapy
Genes
Fluorouracil
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. / Adachi, Yoshiaki; Tamiya, Takashi; Ichikawa, Tomotsugu; Terada, Kin'ya; Ono, Yasuhiro; Matsumoto, Kengo; Furuta, Tomohisa; Hamada, Hirofumi; Ohmoto, Takashi.

In: Human Gene Therapy, Vol. 11, No. 1, 2000, p. 77-89.

Research output: Contribution to journalArticle

Adachi, Yoshiaki ; Tamiya, Takashi ; Ichikawa, Tomotsugu ; Terada, Kin'ya ; Ono, Yasuhiro ; Matsumoto, Kengo ; Furuta, Tomohisa ; Hamada, Hirofumi ; Ohmoto, Takashi. / Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine. In: Human Gene Therapy. 2000 ; Vol. 11, No. 1. pp. 77-89.
@article{c07f1cf7086e4571ab537d54ad7d13cb,
title = "Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine",
abstract = "Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.",
author = "Yoshiaki Adachi and Takashi Tamiya and Tomotsugu Ichikawa and Kin'ya Terada and Yasuhiro Ono and Kengo Matsumoto and Tomohisa Furuta and Hirofumi Hamada and Takashi Ohmoto",
year = "2000",
doi = "10.1089/10430340050016175",
language = "English",
volume = "11",
pages = "77--89",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "1",

}

TY - JOUR

T1 - Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine

AU - Adachi, Yoshiaki

AU - Tamiya, Takashi

AU - Ichikawa, Tomotsugu

AU - Terada, Kin'ya

AU - Ono, Yasuhiro

AU - Matsumoto, Kengo

AU - Furuta, Tomohisa

AU - Hamada, Hirofumi

AU - Ohmoto, Takashi

PY - 2000

Y1 - 2000

N2 - Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.

AB - Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.

UR - http://www.scopus.com/inward/record.url?scp=0033958068&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033958068&partnerID=8YFLogxK

U2 - 10.1089/10430340050016175

DO - 10.1089/10430340050016175

M3 - Article

C2 - 10646641

AN - SCOPUS:0033958068

VL - 11

SP - 77

EP - 89

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 1

ER -