Yeast cytosine deaminase (yCD), a zinc metalloenzyme, catalyzes the hydrolytic deamination of cytosine to uracil. The enzyme is of great biomedical interest because it also catalyzes the deamination of the prodrug 5-fluorocytosine (5FC) to form the anticancer drug 5-fluorouracil (5FU). yCD/5FC is one of the most widely used enzyme/prodrug combinations for gene-directed enzyme prodrug therapy fo...

Generating a phosphate prodrug is one of the common approaches for circumventing poor solubility issues of a parent drug. Alkaline phosphatase (ALP) level was determined in rat intestine mucosa scraps, human colon carcinoma (Caco-2) cells, and Madin-Darby canine kidney (MDCK) cells to characterize in vitro models for ALP-mediated phosphate prodrug conversion. In addition, fosphenytoin and fosfl...

Escherichia coli nitroreductase (NTR) activates the prodrug CB1954 to a cytotoxic derivative, allowing selective sensitization of NTR-expressing cells or tumors to the prodrug. This is one of several enzyme-prodrug combinations that are under development for cancer gene therapy, and the system has now entered clinical trials. Enhancing the catalytic efficiency of NTR for CB1954 could improve it...

The design, synthesis, and initial biological evaluation of a doxorubicin prodrug that contains a dual tumor specific moiety, which allows enhanced tumor recognition potential, is reported. Both a tumor-specific recognition site and a tumor selective enzymatic activation sequence are incorporated in the prodrug. The first tumor-specific sequence is the bicyclic CDCRGDCFC (RGD-4C) peptide that s...

Gene-directed enzyme prodrug therapy can be used to increase the therapeutic activity of anti-cancer prodrugs that undergo liver cytochrome P450 (CYP)-catalyzed prodrug to active drug conversion. The present report describes a cell-culture-based assay to identify CYP gene-CYP prodrug combinations that generate bystander cytotoxic metabolites and that may potentially be useful for CYP-based gene...

Antibody-directed enzyme prodrug therapy (ADEPT) using anti-TAG-72 antibody and geldanamycin (GA) prodrug were validated in vitro. To understand the complexity and to explore optimal therapeutic regimens for ADEPT in vivo, a physiologically based pharmacokinetic model (PBPK) is applied to analyze each anatomical component/organ. The baseline model predicts that active drug tumor/plasma exposure...

UNIVERSITY OF TURKU Department of Chemistry/ Faculty of Mathematics and Natural Sciences KIURU, EMILIA: Nucleotides as Antiviral Compounds: On the Feasibility of an Esterase-dependent Prodrug Strategy for 2-5A Doctoral thesis, 172 p. Laboratory of Organic Chemistry and Chemical Biology June 2015 Analogues of nucleotides and oligonucleotides have a significant role in the antiviral therapy. Thes...

Molecular logic gates are increasingly important in attributing chemical reactivity to molecular devices. Specific input signals of basic logic gates can be programmed into single molecules that generate readable output signals, such as fluorescence or UV/Vis light. Here we show that the release of an active drug molecule through a prodrug activation process is a viable output signal. The term ...

The efficacy of cancer gene therapy depends critically on "bystander effects" by which genetic modification of tumor cells results in killing of unmodified cells in the local microenvironment. In gene-dependent enzyme-prodrug therapy, expression of a prodrug-activating suicide gene is used to generate a cytotoxic metabolite that diffuses to nontransduced cells. The objective of this study was t...

In this work, the copolymer-based synthesized Cysteine-loaded nanocarriers prepared by a routine protocol, coprecipitation method. It is the first report to investigate the neuroprotective potential and biocompatibility of Cysteine derivatives loaded into poly(ethylene glycol)-block-poly(ε−caprolactone) methyl ether (PEG-b-PCL). The average size of the polymeric/empty NCs was 89 nm and for poly...