Gene-Directed Enzyme Prodrug Cancer Therapy

Karjoo, Zahra; Ganapathy, Vidya; Hatefi, Arash

doi:10.1016/b978-0-12-394295-1.00006-8

Cited by 9 publications

(22 citation statements)

References 121 publications

(136 reference statements)

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“…Until early 2000s, variety of cancer/tissue specific promoters such as human telomerase reverse transcriptase (hTERT) promoter, carcinoembryonic antigen (CEA) promoter, osteocalcin promoter (OC), and hypoxia and radiation responsive elements had been developed [18–21]. The application, advantages and disadvantages of using these promoters are eloquently reviewed by several groups [16, 22, 23], and summarized in a book chapter by our group [24]. Over the past decade, several new promising promoters have been developed which attracted significant attention (Table 1).…”

Section: Cancer Gene Therapymentioning

confidence: 99%

“…Examples of this group include thymidine kinase (TK, Viral), cytosine deaminase (CD, bacterial and yeast), carboxypeptidase G2 (CPG2, bacterial) and nitroreductase (NTR, bacterial) [40]. In contrast to the first group, enzymes in this group are more likely to be immunogenic but there is less probability for observing toxicity in non-target tissues [24]. In general, the expression of enzyme should not be a metabolic burden for the cell housekeeping activities and should show a higher affinity to prodrug than enzyme’s natural substrate.…”

Section: Pillars Of Suicide Gene Therapymentioning

confidence: 99%

“…To remain focused, we have refrained from elaboration on the history, use of less common enzyme/prodrug systems and also application of enzyme/prodrug systems in cancer imaging which can be found elsewhere [24, 53]. An overview of the most widely used enzyme/prodrug systems is presented in Table 2.…”

Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

“…The most common promoters which have been used to enhance the expression of suicide genes at the target tumor site are human telomerase reverse transcriptase (hTERT) promoter, carcinoembryonic antigen (CEA) promoter, osteocalcin promoter (OC), and hypoxia and radiation responsive elements [18–21, 24]. The last reported clinical trial using this approach was conducted by Kubo et al which goes back to year 2003.…”

Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

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

Karjoo

Chen

Hatefi

2016

Advanced Drug Delivery Reviews

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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: Cancer Gene Therapymentioning

confidence: 99%

Section: Pillars Of Suicide Gene Therapymentioning

confidence: 99%

Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

Section: Enzyme/prodrug Systems: From Bench To Bedmentioning

confidence: 99%

See 2 more Smart Citations

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

Karjoo

Chen

Hatefi

2016

Advanced Drug Delivery Reviews

Self Cite

156

168

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“…Unfortunately, in many cases no clear rationale is provided to justify the use of one enzyme/prodrug system over another and it has been unclear which enzyme/prodrug system is the most effective one. As we have discussed elsewhere and knowing that each enzyme/prodrug system has its own strengths and weaknesses[13], it is important to be able to perform a study at the preclinical level that can reliably illustrate the strengths and weaknesses of using different enzyme/prodrug systems and/or compare the efficacies of different enzyme mutants.…”

Section: Introductionmentioning

confidence: 99%

Genetically engineered theranostic mesenchymal stem cells for the evaluation of the anticancer efficacy of enzyme/prodrug systems

Nouri

Wang

Hatefi

2015

Journal of Controlled Release

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Over the past decade, various enzyme/prodrug systems such as thymidine kinase/ganciclovir (TK/GCV), yeast cytosine deaminase/5-fluorocytosine (yCD/5-FC) and nitroreductase/CB1954 (NTR/CB1954) have been used for stem cell mediated suicide gene therapy of cancer. Yet, no study has been conducted to compare and demonstrate the advantages and disadvantages of using one system over another. Knowing that each enzyme/prodrug system has its own strengths and weaknesses, we utilized mesenchymal stem cells (MSCs) as a medium to perform for the first time a comparative study that illustrated the impact of subtle differences among these systems on the therapeutic outcome. For therapeutic purposes, we first genetically modified MSCs to stably express a panel of four suicide genes including TK (TK007 and TKSR39 mutants), yeast cytosine deaminase: uracil phosphoribosyltransferase (yCD:UPRT) and nitroreductase (NTR). Then, we evaluated the anticancer efficacies of the genetically engineered MSCs in vitro and in vivo by using SKOV3 cell line which is sensitive to all four enzyme/prodrug systems. In addition, all MSCs were engineered to stably express luciferase gene making them suitable for quantitative imaging and dose-response relationship studies in animals. Considering the limitations imposed by the prodrugs’ bystander effects, our findings show that yCD:UPRT/5-FC is the most effective enzyme/prodrug system among the ones tested. Our findings also demonstrate that theranostic MSCs are a reliable medium for the side-by-side evaluation and screening of the enzyme/prodrug systems at the preclinical level. The results of this study could help scientists who utilize cell-based, non-viral or viral vectors for suicide gene therapy of cancer make more informed decisions when choosing enzyme/prodrug systems.

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