Antitumor activity of mutant bacterial cytosine deaminase gene for colon cancer

Deng, Ling-Xiao; Wang, Jianping; Gui, Zhifu; Shen, Lizong

doi:10.3748/wjg.v17.i24.2958

Cited by 13 publications

(11 citation statements)

References 24 publications

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“…Kaliberova et al (2008), reported the sequence of a mutant, bCD-D314A, which showed a significant specificity towards 5-FC with a lower IC 50 in comparison to wt-bCD. This mutant has been successfully used in combination with low dose radiation to reduce tumor sizes in various cancer models [91, 92]. Another mutant, reported by Fuchita et al (2009), has showed the most desirable features for suicide gene therapy in terms of significant shift to 5-FC, decrease in IC 50 and an outstanding bystander effect compared to wt-CD[93].…”

Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

Progress and problems with the use of suicide genes for targeted cancer therapy

Karjoo

Chen

Hatefi

2016

Advanced Drug Delivery Reviews

156

168

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Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated.

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Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

Progress and problems with the use of suicide genes for targeted cancer therapy

Karjoo

Chen

Hatefi

2016

Advanced Drug Delivery Reviews

156

168

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“…The same AdbCD-D314A vectors were also used to treat pancreatic cancer cells and similar results with mutant D314A displaying increased tumor killing in vitro and in vivo were seen [79]. Deng et al (2011) showed similar improvements using human colon cancer xenograft models after lentiviral delivery of bCD-D314A and 5FC treatments [80]. …”

Section: Suicide Gene/prodrug Therapy For Cancermentioning

confidence: 90%

Enzymes To Die For: Exploiting Nucleotide Metabolizing Enzymes for Cancer Gene Therapy

Ardiani¹,

Johnson²,

Ruan³

et al. 2012

CGT

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Suicide gene therapy is an attractive strategy to selectively destroy cancer cells while minimizing unnecessary toxicity to normal cells. Since this idea was first introduced more than two decades ago, numerous studies have been conducted and significant developments have been made to further its application for mainstream cancer therapy. Major limitations of the suicide gene therapy strategy that have hindered its clinical application include inefficient directed delivery to cancer cells and the poor prodrug activation capacity of suicide enzymes. This review is focused on efforts that have been and are currently being pursued to improve the activity of individual suicide enzymes towards their respective prodrugs with particular attention to the application of nucleotide metabolizing enzymes in suicide cancer gene therapy. A number of protein engineering strategies have been employed and our discussion here will center on the use of mutagenesis approaches to create and evaluate nucleotide metabolizing enzymes with enhanced prodrug activation capacity and increased thermostability. Several of these studies have yielded clinically important enzyme variants that are relevant for cancer gene therapy applications because their utilization can serve to maximize cancer cell killing while minimizing the prodrug dose, thereby limiting undesirable side effects.

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“…4. Also, dosing of 5-FC might have been suboptimal under our current regime applying a 5-FC standard dose of 500 mg/kg body weight, which is quite often used in mouse xenograft tumor models (You et al, 2009;Deng et al, 2011). However, in a recent preclinical study (Erbs et al, 2008) animal groups treated with adenovirus-based vectors (Ad-FCU1) exhibited statistically significant differences in tumor sizes between the group treated with Ad-FCU1 plus 5-FC and the other groups only when 5-FC was given at 1,000 mg/kg body weight per day.…”

Section: Discussionmentioning

confidence: 99%

A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma

Lange¹,

Lampe²,

Zimmermann³

et al. 2012

Z Gastroenterol

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Cholangiocarcinoma (CC) is curable only in early stages by complete surgical resection. Thus, in advanced disease stages in which a complete removal of the tumor mass is no longer possible and palliative chemotherapy achieves only modest success, therapeutics employing new methods of action are desperately needed. Oncolytic viruses employed in clinical studies have been shown to spread preferentially in cancer cells. Beyond that, virotherapeutic cell killing can be enhanced by virus-based expression of suicide genes. We engineered a measles vaccine virus (MeV) vector expressing super cytosine deaminase (SCD), a fusion protein of yeast cytosine deaminase and uracil phosphoribosyltransferase, which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) and subsequently to 5-fluorouridine-monophosphate. This novel vector was evaluated using three different human-derived CC cell lines. In vitro, all CC cell lines were found to be permissive to MeV infection. Partial blocking of MeV-mediated oncolysis could be overcome by employment of the SCD transgene together with administration of 5-FC. In vivo, intratumoral application of SCD-armed MeV together with a systemic 5-FC treatment showed a significant reduction in tumor size in a TFK-1 xenograft mouse model when compared with virus-only treatment. In a second animal experiment employing a HuCCT1 xenograft tumor model, an enhanced SCD-armed MeV vector, in which the SCD transgene was expressed from a different genomic position, led not only to reduced tumor volumes, but also to a significant survival benefit. On the basis of these encouraging preclinical data on employment of SCD-armed MeV for the virotherapeutic treatment of chemotherapy-resistant CC, a clinical virotherapy trial is set up currently.

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Antitumor activity of mutant bacterial cytosine deaminase gene for colon cancer

Abstract: The bCD mutant D314A enhanced significantly antitumor activity in human colon cancer xenograft models, which provides a promising approach for human colon carcinoma therapy.

Cited by 13 publications

References 24 publications

Progress and problems with the use of suicide genes for targeted cancer therapy

Progress and problems with the use of suicide genes for targeted cancer therapy

Enzymes To Die For: Exploiting Nucleotide Metabolizing Enzymes for Cancer Gene Therapy

A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma

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