Apoptosis Induction With 5-Fluorocytosine/Cytosine Deaminase gene Therapy for Human Malignant Glioma Cells Mediated by Adenovirus

Kurozumi, Kazuhiko; Tamiya, Takashi; Ono, Yasuhiro; Otsuka, Shinji; Kambara, Hirokazu; Adachi, Yoshiaki; Ichikawa, Tomotsugu; Hamada, Hirofumi; Ohmoto, Takashi

doi:10.1023/b:neon.0000013494.98345.80

Cited by 37 publications

(26 citation statements)

References 41 publications

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“…These data agree with observations that induction of apoptosis, DNA damage, activation of mitochondrial caspase pathway involving caspases-3 and -9, and inhibition of TS and DNA synthesis are associated with CD/5-FC-mediated glioma 30 and pancreatic 31 cancer cell killing. Combined treatment using Ad-CD:UPRT-mediated coda:upp suicide genes with TRA-8, which strongly induces apoptosis of most TRAIL-sensitive tumor cells both in vitro and in vivo, 8,10,32 led to an enhanced and sustained activation of apoptosis in cancer cells.…”

Section: Discussionsupporting

confidence: 92%

Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity

et al. 2005

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Combined treatment using adenoviral-directed enzyme/prodrug therapy and immunotherapy has the potential to become a powerful alternative method of cancer therapy. We have developed adenoviral vectors encoding the cytosine deaminase gene (Ad-CD) and cytosine deaminase:uracil phosphoribosyltransferase fusion gene (Ad-CD:UPRT). A monoclonal antibody, TRA-8, specifically binds to death receptor 5, one of two death receptors bound by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of Ad-CD:UPRT and TRA-8 against human pancreatic cancer and glioma cell lines. The present study demonstrates that Ad-CD:UPRT infection resulted in increased 5-FC-mediated cell killing, compared with Ad-CD. Furthermore, a significant increase of cytotoxicity following Ad-CD:UPRT/5-FC and TRA-8 treatment of cancer cells in vitro was demonstrated. Animal studies showed significant inhibition of tumor growth of MIA PaCa-2 pancreatic and D54MG glioma xenografts by the combination of Ad-CD:UPRT/5-FC plus TRA-8 as compared with either agent alone or no treatment. The results suggest that the combination of Ad-CD:UPRT/5-FC with TRA-8 produces an additive cytotoxic effect in cancer cells in vitro and in vivo. These data indicate that combined treatment with enzyme/prodrug therapy and TRAIL immunotherapy provides a promising approach for cancer therapy.

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Section: Discussionsupporting

confidence: 92%

Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity

et al. 2005

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“…1,2,[21][22][23][24][25] However, these models have limited value in predicting the therapeutic effectiveness in a clinical context. The poor predictive value of these model systems arises from the great differences that exist between primary tumor cells and the tumor cell lines developed for research.…”

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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“…Adenoviral (Ad)-mediated CD gene therapy have been widely studied for glioma treatment in vitro and in animal tumor models. [5][6][7][8][9] A major problem associated with this suicide GDEPT approach is the low affinity displayed by the CD gene product toward 5-FC in comparison with cytosine. Thus, high doses of this prodrug must be administered in order to achieve cell killing.…”

Section: Introductionmentioning

confidence: 99%

Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma

et al. 2007

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Combined treatment using adenoviral (Ad)-directed enzyme/ prodrug therapy and radiation therapy has the potential to become a powerful method of cancer therapy. We have developed an Ad vector encoding a mutant bacterial cytosine deaminase (bCD) gene (AdbCD-D314A), which has a higher affinity for cytosine than wild-type bCD (bCDwt). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of AdbCD-D314A with the prodrug 5-fluorocytosine (5-FC) and ionizing radiation against human glioma. The present study demonstrates that AdbCD-D314A infection resulted in increased 5-FC-mediated cell killing, compared with AdbCDwt. Furthermore, a significant increase in cytotoxicity following AdbCD-D314A and radiation treatment of glioma cells in vitro was demonstrated as compared to AdbCDwt. Animal studies showed significant inhibition of subcutaneous or intracranial tumor growth of D54MG glioma xenografts by the combination of AdbCD-D314A/5-FC with ionizing radiation as compared with either agent alone, and with AdbCDwt/5-FC plus radiation. The results suggest that the combination of AdbCD-D314A/5-FC with radiation produces markedly increased cytotoxic effects in cancer cells in vitro and in vivo. These data indicate that combined treatment with this novel mutant enzyme/prodrug therapy and radiotherapy provides a promising approach for cancer therapy.

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Apoptosis Induction With 5-Fluorocytosine/Cytosine Deaminase gene Therapy for Human Malignant Glioma Cells Mediated by Adenovirus

Cited by 37 publications

References 41 publications

Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity

Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity

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

Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma

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