Antineoplastic Effect of 5-Fluorocytosine and Cytosine Deaminase on Brain Tumor

Nishiyama, T.; Kawamura, Yasuo; Kawamoto, Keiji; Matsumura, Hiroshi; Yamamoto, Norimi; Ito, Toshiko; Ohyama, Akio; Katsuragi, Toru; Sakai, Taku

doi:10.2176/nmc.22.344

Cited by 40 publications

(58 citation statements)

References 20 publications

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“…However, most clinical studies with 5-FU alone have indicated no value in the treatment of patients with malignant gliomas. 33 The primary limitation of systemic chemotherapy is due to a low therapeutic index. To overcome this problem, in vivo suicide gene therapy has the theoretical advantage of delivering high local concentrations of a therapeutic agent while minimizing systemic side-effects, resulting in increases in the therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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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 Ͼ90 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. Cancer Gene Therapy (2000) 7, 74 -82

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Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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“…These vectors have previously shown high efficacy on glioblastoma cell lines, suggesting a potential for the treatment of cancers of the central nervous systems, 10 and possibly cancers of other origins. Through the actions of CD, an enzyme that is present in prokaryotes and fungi but not in multicellular eukaryotes, 11,12 the benign pro-drug 5-FC is converted to the highly cytotoxic 5-FU. 5-FC is introduced at relatively high concentrations, thus allowing the 5-FU generated at the tumor site to achieve concentrations that are higher than can be systemically administered safely.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

et al. 2006

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A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CDHUPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CDHUPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.

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“…The first trial employing the 5 -FC /CD system for malignancy was described in 1985. 4 This gene therapy utilizing adenovirus vectors has been applied to several types of solid tumors, including colorectal, 5,6 gastric, 7 and hepatocellular cancers, 8 as well as gliomas. 1,9 Transduction of the UPRT gene has been reported to enhance chemosensitivity to 5 -FU or 5 -FC through the activation pathway to 5-FU.…”

Section: Discussionmentioning

confidence: 99%

Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes

et al. 2002

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Antineoplastic Effect of 5-Fluorocytosine and Cytosine Deaminase on Brain Tumor

Cited by 40 publications

References 20 publications

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

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

Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes

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