NCIt definition : An orally bioavailable glucuronide prodrug of TSL-1502M, an inhibitor of the nuclear
enzyme poly(ADP-ribose) polymerase (PARP), with potential chemo/radiosensitizing and
antineoplastic activities. Upon oral administration, prodrug PARP inhibitor TSL-1502
is selectively converted by the enzyme beta-glucuronidase in the tumor microenvironment
(TME) to its active form TSL-1502M. TSL-1502M selectively targets and binds to PARP
and prevents PARP-mediated DNA repair of DNA breaks via the base-excision repair pathway.
This enhances the accumulation of DNA strand breaks and promotes genomic instability
and eventually leads to G2/M arrest and apoptosis. This may enhance the cytotoxicity
of DNA-damaging agents. PARP catalyzes post-translational ADP-ribosylation of nuclear
proteins that signal and recruit other proteins to repair damaged DNA and is activated
by DNA breaks. The PARP-mediated repair pathway is dysregulated in a variety of cancer
cell types. Beta-glucuronidase accumulates in the TME upon release from necrotic tumor
cells and certain inflammatory cells.;
Semantic type(s)