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New chemotherapy more selective.

One of the largest challenges of chemotherapy lies in the fact that cancer cells need to be killed while healthy tissue must be protected. French researchers have introduced a new approach in Angewandte Chemie: the enzyme B-galactosidase releases the active drug from an inactive precursor, known as a prodrug, which only can be taken up by tumor cells.

A number of tumor-specific markers have been found over the years. These are receptors that are commonly located in the cell membranes of tumor cells, but are absent from, or rare, on the surfaces of healthy cells. Previously, researchers mostly have used antibodies directed toward these receptors to deliver drugs selectively to tumor cells. The disadvantages of this method not only are the high cost and difficult development and production, but the inherent risk of undesired immune responses.

A team led by Sebastien Papot at the University of Poitiers, France, has 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 fuses with lysosomes, cell organelles whose contents include the enzyme B-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 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 often are made of different types of cells that may not all have the right receptor. More distant, healthy cells are not affected. They also are not able to take up the prodrug because they do not have the special receptors.

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Title Annotation:Cancer Cells
Publication:USA Today (Magazine)
Geographic Code:4EUFR
Date:Feb 1, 2013
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