One of the largest challenges of chemotherapy lies in the fact that
cancer cells must be killed while healthy tissue must be protected.
French researchers have now introduced a new approach in the journal
Angewandte Chemie: The enzyme β-galactosidase releases the active drug
from an inactive precursor, known as a prodrug, which can only be taken
up by tumor cells.
A number of tumor-specific markers have been found over the years. These
are receptors that are commonly found in the cell membranes of tumor
cells but are absent from or rare on the surfaces of healthy cells.
Previously, researchers have mostly used antibodies directed toward
these receptors to deliver drugs selectively to tumor cells. The
disadvantages of this method are not only the high cost and difficult
development and production, but also the inherent risk of undesired
immune responses.
A team led by Sébastien Papot at the University of Poitiers has now
developed a simpler approach that works without antibodies. It is based
on a prodrug with four components: the actual cytotoxic agent, a ligand
that recognizes one of the tumor-specific receptors, a “trigger” for the
release, and a linker that holds everything together.
In the first step, the ligand binds to the tumor-specific receptor on
the surface of a tumor cell. The tumor cell then folds its membrane in
to enclose the receptor and prodrug in a bubble and bring them into the
cell (receptor-mediated endocytosis). This bubble then fuses with
lysosomes, cell organelles whose contents include the enzyme
β-galactosidase. This enzyme splits galactose off of polysaccharides.
The trigger portion of the prodrug is a galactose unit. As soon as the
enzyme splits it off, the linker undergoes a spontaneous decomposition
that releases and activates the drug. The drug kills the tumor cell by
inhibiting cell division.
In addition, the drug also escapes the actual tumor cell and is absorbed
by immediate neighbors—even if they do not have the tumor-specific
receptor on their membrane—killing them as well. This is useful because
tumors are often made of different types of cells that may not all have
the right receptor. More distant, healthy cells are not affected. They
are also not able to take up the prodrug because they do not have the
special receptors.
Initial animal trials with a prodrug based on this principle showed it
to be very effective. The tumors shrank when treated with the prodrug,
whereas administration of the free cytostatic was not very effective.
Registered journalists may download the original article here:
The
First Generation of β-Galactosidase-Responsive Prodrugs Designed for the
Selective Treatment of Solid Tumors in Prodrug Monotherapy
Contact: Sébastien Papot, Université de Poitiers (France)