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May 2, 2005

USC researchers determine mechanism of action of motexafin gadolinium (Xcytrin)

Topics: Clinical Pharmacology

The chemotherapy drug motexafin gadolinium (brand name: Xcytrin, manufactured by Pharmacyclics, Inc) works to thwart cancer cells by disrupting key enzymes involved in cellular metabolism, according to a team of researchers led by Joseph Hacia, Ph.D., assistant professor of biochemistry and molecular biology at the Keck School of Medicine of the University of Southern California.

(...) The cellular disruption results in increases in the amount of zinc available inside the cancer cells, and because zinc is involved in protein structure and function, leads to inhibition of enzyme activity and to the death of the cells.

(...) the researchers looked at gene expression profiles and other biochemical properties of cells from human lung, prostate and lymphoma cancer cell cultures that had been treated with motexafin gadolinium, or MGd. What they found was that the drug created oxidative stress in the tumor cells, increasing the levels of expression of the genes that produce metallothioneins.

(...) the increased metallothionein expression levels resulted from significantly increased levels of free-i.e., not protein-bound-zinc in the cells. The zinc, in turn, acted to inhibit an enzyme-thioredoxin reductase-that is an important component in the cell's antioxidant system, as well as important in DNA synthesis. In other words, thioredoxin reductase is key to the replication and survival of cells, and its inhibition ultimately leads to cell death.

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Related reading:

Motexafin gadolinium: a redox-active tumor selective agent for the treatment of cancer.

Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species.

Posted by Richard at May 2, 2005 8:46 AM


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