Selective tumor treatment: β-galactosidase releases active agent from prodrugs

October 9, 2012, Wiley

(Phys.org)—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 that are commonly found in the cell membranes of 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 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.

Explore further: Selectively stopping glutathione sensitizes brain tumors to chemotherapy

More information: Sébastien Papot, "The First Generation of β-Galactosidase-Responsive Prodrugs Designed for the Selective Treatment of Solid Tumors in Prodrug Monotherapy." Angewandte Chemie International Edition, dx.doi.org/10.1002/anie.201204935

Related Stories

Cell receptor could allow measles virus to target tumors

August 25, 2011

Canadian researchers have discovered that a tumor cell marker is a receptor for measles virus, suggesting the possible use of measles virus to help fight cancer. Their findings appear in the Open Access journal PLoS Pathogens ...

Tumor environment keeps tumor-fighting T cells away

September 19, 2011

Tumors have an arsenal of tricks to help them sidestep the immune system. A study published on September 19 in the Journal of Experimental Medicine reveals a new trick -- the ability to keep tumor-fighting T cells out by ...

New universal platform for cancer immunotherapy developed

March 5, 2012

(Medical Xpress) -- Researchers from the Perelman School of Medicine at the University of Pennsylvania report this month in Cancer Research a universal approach to personalized cancer therapy based on T cells. It is the first ...

Recommended for you

Bio-renewable process could help 'green' plastic

January 19, 2018

When John Wesley Hyatt patented the first industrial plastic in 1869, his intention was to create an alternative to the elephant tusk ivory used to make piano keys. But this early plastic also sparked a revolution in the ...

Simulations show how atoms behave inside self-healing cement

January 19, 2018

Researchers at Pacific Northwest National Laboratory (PNNL) have developed a self-healing cement that could repair itself in as little as a few hours. Wellbore cement for geothermal applications has a life-span of only 30 ...

Looking to the sun to create hydrogen fuel

January 18, 2018

When Lawrence Livermore scientist Tadashi Ogitsu leased a hydrogen fuel-cell car in 2017, he knew that his daily commute would change forever. There are no greenhouse gases that come out of the tailpipe, just a bit of water ...

A new polymer raises the bar for lithium-sulfur batteries

January 18, 2018

Lithium-sulfur batteries are promising candidates for replacing common lithium-ion batteries in electric vehicles since they are cheaper, weigh less, and can store nearly double the energy for the same mass. However, lithium-sulfur ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Birger
not rated yet Oct 09, 2012
Kudos to the team! I hope the path to clinical trials will be smooth.
dschlink
not rated yet Oct 09, 2012
An amazing bit of work.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.