Targeted Enzyme Prodrug Therapies

Abstract

The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

Synthesis of Heterobifunctional Protein Fusions Using Copper‐Free Click Chemistry and the Aldehyde Tag

“…[46][47][48] Furthermore, the approach can be extended to protein-synthetic polymer conjugations and surface immobilization [49,50] along with designing protein conjugates that extend serum halflife, [51] or for vaccine development. [52] Experimental Section General protein conjugation: A buffered solution (optimal pH 4.5) of aldehyde-tagged protein (10-50 mm) was treated with aminooxy reagent (0.2-1 mm, 10-20 equiv) and agitated at 35 8C for 16 h. Proteins were purified from low molecular weight reagents by buffer exchange or analyzed directly by SDS-PAGE.…”

A Fusion Protein of RGD4C and β-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy

“…ADEPT combining the high affinity and specificity of monoclonal antibodies and high catalytic activity of enzymes, which can restrict the action of cytotoxic drugs into tumor site, has become a promising approach for tumor treatment and derived a variety of related modalities [18]. Conjugates used in enzyme prodrug therapy, which consist by enzymes coupled with targeting molecules, require certain characteristics such as good stability, low immunogenicity, ease of manufacturing, and no substrates or inhibitors in human body.…”

Concerning RNA-Guided Gene Drives for the Alteration of Wild Populations

“…First, a sensitizing drive might reverse known mutations that confer resistance to existing pesticides or herbicides. Second, it might carry a prodrug-converting enzyme 99 that would render a prodrug molecule toxic to organisms that express it. Third, it could swap a conserved gene for a version that is strongly inhibited by a particular small molecule.…”