Synthesis and Biological Evaluation of Prodrugs Based on the Natural Antibiotic Duocarmycin for Use in ADEPT and PMT

Tietze, Lutz F.; Schmuck, Kianga; Müller, Michael; Schuberth, Ingrid

doi:10.1002/chem.201002798

Cited by 26 publications

(19 citation statements)

References 57 publications

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“…One such prodrug is a duocarmycin SA analog (Tietze et al, 2011), which selectivity binds the N3 of adenine in AT rich-minor DNA groove regions. Duocarmycin SA is one of the strongest known anticancer compounds, but even analogs trigger severe myelotoxicity (Hurley et al, 1988;Puyo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Guillen

Ruben

Virani

et al. 2016

Protein Engineering, Design and Selection

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Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting. To create fusion proteins, human annexin A1/A5 was genetically fused to the activity-enhancing 16a3 mutant of human βG, expressed in chemically defined, fed-batch suspension culture, and chromatographically purified. All fusion constructs achieved >95% purity with yields up to 740 μg/l. Fusion proteins displayed cancer selective cell-surface binding with cell line-dependent binding stability. One fusion protein in combination with the prodrug SN-38 glucuronide was as effective as the drug SN-38 on Panc-1 pancreatic cancer cells and HAAE-1 endothelial cells, and demonstrated efficacy against MCF-7 breast cancer cells. βG fusion proteins effectively enable localized combination therapy that can be tailored to each patient via prodrug selection, with promising clinical potential based on their near fully human design.

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Section: Discussionmentioning

confidence: 99%

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Guillen

Ruben

Virani

et al. 2016

Protein Engineering, Design and Selection

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“…The active moiety or tumor‐associated antigen‐specific monoclonal antibody of ADPET and PMT is efficiently released by the action of specific enzymes expressed at high levels in tumor tissues . It was found that α‐mannosidase activity and β‐galactosidase activity are elevated in certain cancer types, such as breast cancer, gliomas, leukemias, colon cancer, bladder cancer, larynx cancer, and ovarian cancer . The case is similar for l ‐fucosidase activity in breast cancer, leukemia, and ovarian cancer .…”

Section: Targeting Properties Of Mono‐ and Disaccharidesmentioning

confidence: 94%

“…[46] Therefore, carbohydrates, including mono-o rd isaccharides, were incorporated into nonspecific antitumor compounds to improve their specificity and efficacy.The active moiety or tumor-associated antigen-specific monoclonal antibody of ADPET and PMT is efficiently released by the action of specific enzymes expressed at high levels in tumor tissues. [46][47][48] It wasf ound that a-mannosidase activity and b-galactosidasea ctivity are elevated in certain cancer types, such as breast cancer, [49] gliomas, [50] leukemias, [51] colon cancer, [52] bladder cancer, [47] larynx cancer, [53] and ovarian cancer. [54] The case is similar for l-fucosidase activity in breast cancer, [47] leukemia, [55] and ovarian cancer.…”

Section: Cancermentioning

confidence: 99%

“…[46][47][48] It wasf ound that a-mannosidase activity and b-galactosidasea ctivity are elevated in certain cancer types, such as breast cancer, [49] gliomas, [50] leukemias, [51] colon cancer, [52] bladder cancer, [47] larynx cancer, [53] and ovarian cancer. [54] The case is similar for l-fucosidase activity in breast cancer, [47] leukemia, [55] and ovarian cancer. [54] Therefore, galactose, mannose, fucose,a nd other hexoses were found to be good carriers or ligandsf or site-specific substrates for the aforementioned glycosidase activity in drug design.…”

Section: Cancermentioning

confidence: 99%

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Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

Yuan

Chen

et al. 2018

ChemMedChem

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Carbohydrates and their conjugates play important roles in many biological processes including fertilization, differentiation, development, immune response, and infection. Their activities are largely dependent on the properties of terminal mono- or disaccharides. Galactose, mannose, fucose, glucose, sialic acid, etc., are commonly used as powerful scaffolds installed on drug molecules for targeting specific tissues including brain, liver, and cancers, and as epitopes for enhancing the targeting of various vaccines. This review focuses on the influence of their structural variations, including changes in sugar type, substituent groups and their positions, as well as length of linker portion, on the targeting of drugs or their efficacy. Particular attention is paid to the targeting properties of mono- and disaccharides applied in drug design and discovery.

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“…In this context, numerous glucuronide prodrugs (Grinda et al 2011(Grinda et al , 2012Thomas et al 2008;Tietze et al 2011) that can be activated by β-glucuronidase present in the tumor microenvironment (Bosslet et al 1995;Connors and Whisson 1966) have been investigated to enhance the selectivity of cancer chemotherapy. The β-glucuronidase is a lysosomal enzyme released mainly by the immune and inflammatory cells of the necrotic area (Bosslet et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

et al. 2014

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

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Synthesis and Biological Evaluation of Prodrugs Based on the Natural Antibiotic Duocarmycin for Use in ADEPT and PMT

Cited by 26 publications

References 57 publications

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

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