Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Afshar, Sepideh; Asai, Tomohisa; Morrison, Sherie L.

doi:10.1158/1535-7163.mct-08-0652

Cited by 32 publications

(38 citation statements)

References 43 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Metabolites from PNP are incorporated during RNA synthesis and hence eventually block protein synthesis. Limitations related to immunogenicity from the bacterial PNP led investigators to develop human PNP (hPNP) mutants that can cleave adenosine based prodrugs which are not recognized by wild-type hPNP [135]. These mutants are an attractive target because the endogenous wild-type hPNP cannot use (deoxy) adenosine-based prodrugs as substrate, whereas the mutants are highly effective in cleaving (deoxy) adenosine-based prodrugs and generating high levels of cytotoxic drugs in preclinical models [136].…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Limitations due to immunogenicity from the bacterial origins of PNP led investigators to develop human PNP (hPNP) mutants that can cleave adenosine-based prodrugs that are not recognized by wild-type hPNP [87]. These mutants are an attractive target because whereas the endogenous wild-type hPNP cannot use (deoxy)adenosine-based prodrugs as substrate, the mutants are highly effective at cleaving (deoxy)adenosine-based prodrugs and generating high levels of cytotoxic drugs in preclinical models [88,89].…”

Section: Purine Nucleoside Phosphorylase/ 6-methylpurine Deoxyribosidmentioning

confidence: 99%

Gene-Directed Enzyme Prodrug Cancer Therapy

Karjoo

Ganapathy

Hatefi

2014

Gene Therapy of Cancer

View full text Add to dashboard Cite

“…However, bacterial enzymes may elicit an immune response, especially with repeated administration, but, regardless, some bacterial enzymes have been successfully tested in humans, such as carboxypeptidase G2. 42 Immunogenicity of the enzyme in each EPT system may be addressed by 1 of 3 methods: (i) PEGylating the entire fusion protein to restrict immune recognition, 43 (ii) mutating the active site of human analogs of the bacterial enzyme to confer activity towards the corresponding prodrug, 44,45 or by (iii) genetically modifying the immunogenic epitopes found on the bacterial enzyme. 42 Because all of the EPT systems investigated are targeted via AV, the concern exists that in a clinical setting, the intravenously administered fusion proteins could bind to activated platelets, which also express phosphatidylserine.…”

Section: Discussionmentioning

confidence: 99%