methaneselenol and Pancreatic-Neoplasms

Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH₃SeH) being one of the key executors. In search of novel CH₃SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI

Topics: Antineoplastic Agents; cdc42 GTP-Binding Protein; Cell Line, Tumor; Down-Regulation; Entosis; Homeostasis; Humans; Methanol; Organoselenium Compounds; Oxidation-Reduction; Pancreatic Neoplasms; Selenium Compounds

The bleak prognosis associated with pancreatic cancer (PDAC) drives the need for the development of novel treatment methodologies. Here, we evaluate the applicability of 3 enzyme prodrug therapies for PDAC, which are simultaneously targeted to the tumor, tumor vasculature, and metastases via annexin V. In these therapies, annexin V is fused to an enzyme, creating a fusion protein that converts nontoxic drug precursors, prodrugs, into anticancer compounds while bound to the tumor, therefore mitigating the risk of side effects.. The binding strength of fusion proteins to the human PDAC cell lines Panc-1 and Capan-1 was measured via streptavidin-horseradish peroxidase binding to biotinylated fusion proteins. Cytotoxic efficacy was evaluated by treatment with saturating concentrations of fusion protein followed by varying concentrations of the corresponding prodrug plus docetaxel.. All fusion proteins exhibited strong binding to PDAC cells, with dissociation constants between 0.02 and 1.15 nM. Cytotoxic efficacy was determined to be very good for 2 of the systems, both of which achieved complete cell death on at least 1 cell line at physiologically attainable prodrug concentrations.. Strong binding of fusion proteins to PDAC cells and effective cytotoxicity demonstrate the potential applicability of enzyme prodrug therapy to the treatment of PDAC.

Topics: Adenine; Adenocarcinoma; Annexin A5; Antineoplastic Combined Chemotherapy Protocols; Carbon-Sulfur Lyases; Cell Death; Cell Line, Tumor; Cytosine Deaminase; Docetaxel; Dose-Response Relationship, Drug; Enzymes; Flucytosine; Fluorouracil; Humans; Methanol; Molecular Targeted Therapy; Organoselenium Compounds; Pancreatic Neoplasms; Prodrugs; Purine-Nucleoside Phosphorylase; Recombinant Fusion Proteins; Selenomethionine; Taxoids; Tubulin Modulators; Vidarabine