Cancer Drug Targets Tumor Cells

The drug – a DNA methylation inhibitor called zebularine – is better at inhibiting cell growth in cancer cells, said Peter Jones, director of the USC/Norris Comprehensive Cancer Center and the principal investigator on the study.

In a study of zebularine’s effect on the division of cancer cells, Jones and his colleagues showed that zebularine slows growth by as much as 68 percent in cancer cells, but only by 21 percent or less in normal cells.

The findings were reported in the August 2004 issue of Cancer Cell.

Only recently have scientists begun to recognize the important role that DNA methylation – the addition of a methyl group to a stretch of DNA, which can lock, or silence, that gene – can play in the development of cancer.

If methylation silences a gene that normally would control cell growth or prompt the cell to commit suicide, then the cell will grow unchecked – the hallmark of cancer.

The good news: Methylation – and its effects – can be reversible. Enter the emerging field of epigenetic therapy, in which methylation inhibitors are currently playing a starring role.

“The concept that the silencing of genes is a critical part of the cancer process is a major conceptual advance in this field,” Jones said. “Realizing that, it becomes very important to find keys to unlock those silenced genes.”

In the Cancer Cell study, Jones, Cheng and graduate student Christine Yoo – along with colleagues from the National Cancer Institute, the University of Miami School of Medicine and Aarhus University Hospital in Denmark – looked at the effects zebularine had on a panel of seven different human tumor cell lines, and compared them to its effects on four different cell lines of normal human fibroblasts – cells that produce collagen fibers and retain an ability to differentiate and grow.

The difference between tumor cells and normal fibroblasts is that the growth of tumor cells tends to continue unchecked.

What the researchers found was that, in all seven cancer cell lines, treatment with zebularine slowed tumor-cell growth by anywhere between 32 and 68 percent. The fibroblasts, on the other hand, showed only a 12 to 21 percent slowdown.

Much of the difference, Jones noted, comes from the way zebularine is preferentially taken up by the cancer cells. Zebularine appears to bring about this change by demethylating specific genes in the cells – in particular, the p21 gene.

“Our results demonstrate that zebularine can be selective toward cancer cells and may hold clinical promise as an anticancer therapy,” the researchers wrote.

Zebularine’s inhibition of DNA methylation was first discovered in experiments on a filamentous fungus by Eric Selker of the University of Oregon, said Jonathan Cheng, an M.D./Ph.D. student at USC who is one of the first authors on the Cancer Cell paper.

“It was completely unexpected,” Cheng said. “And we have since shown that it can work the same way in mammalian cells.”

In a previous study published in the Journal of the National Cancer Institute in March 2003, Jones and Cheng showed that zebularine can reduce the size of tumors in mice even when given orally, and that it does this tumor-whittling by turning on tumor suppressor genes that had been turned off through methylation.

“This was the first time this type of drug has been able to reactivate silenced genes through oral administration,” Jones said.

The new study published in Cancer Cell not only adds to the optimism surrounding zebularine that was generated by the earlier research, but also creates a renewed sense of hope that, because zebularine is not taken up by cancer and normal cells at the same rate, the drug will be less side-effect laden than other anticancer therapies.

Future work will focus on replicating these results with other normal and tumor cell lines, as well as investigating the specifics behind zebularine’s preferential uptake by the tumor cells, Jones said.