Researchers determine mechanism of action of chemotherapy drug motexafin gadolinium

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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.

A paper describing these findings was published in the May 1, 2005, issue of the journal Cancer Research.

In order to gain a better understanding of the mechanism of action of this novel chemotherapeutic agent, 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 researchers showed that 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.

"Our studies showed that MGd induces oxidative stress in cancer cells," says Hacia, who is a member of USC's Institute for Genetic Medicine, "and this leads to disruption of zinc metabolism and alteration of key enzymes and metabolites necessary for normal cell function."

Thus, the researchers noted, the use of MGd leads to the death of cancer cells via disruption of critical enzymes needed for cell survival and replication.

"We have increased the understanding of this drug's mechanism of action," Hacia said of the study, adding that it also may "provide support for the hypothesis that agents that disrupt metabolism and increase intracellular zinc levels have potential applications as anticancer therapeutics."

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