Magazine article Science News

Double Trouble: Tiny Genetic Loops Aid Cancer Cells, Offer Target for Therapy

Magazine article Science News

Double Trouble: Tiny Genetic Loops Aid Cancer Cells, Offer Target for Therapy

Article excerpt

The compelling tale of Dr. Jekyll and Mr. Hyde endures because it appeals to a reader's fascination with the idea that a murderous monster lurks inside an outwardly normal person. A similar theme--the normal transformed into the deadly--drives the story of cancer.

Mr. Hyde proved difficult to catch in large part because he reassumed the guise of Dr. Jekyll. As for cancer, the body's immune system often fails to recognize tumor cells as dangerous because they retain so many aspects of normal cells. Moreover, those similarities make it difficult to kill tumor cells without damaging healthy tissues in the process.

Consequently, scientists search vigorously for features--surface proteins, gene mutations, enzymes, and so on--that differentiate tumor cells from normal cells and that may eventually be used in the design of therapies that target only cancer cells. Small rings of DNA known as double minute chromosomes may represent one such distinguishing feature.

More than half of all tumors contain these genetic loops, whereas normal cells do not. The minichromosomes usually bear extra copies of genes that are useful to a cancer cell, such as those that override a cell's growth controls or make a cell resistant to drugs used in chemotherapy. Thus, double minute chromosomes seem to increase a tumor cell's chances of surviving and proliferating.

Although scientists have known about these minichromosomes for several decades, they remain relatively obscure. "I think double minute chromosomes have escaped attention because people haven't realized how interesting they are as molecular entities and unique targets for therapy," asserts Geoffrey M. Wahl of the Salk Institute for Biological Studies in La Jolla, Calif.

Wahl hopes to shine a spotlight on these DNA loops. He and his colleagues have recently found a way to track double minute chromosomes in living cells. Other studies by this group help explain how cells shed the chromosomes, a process that may suggest novel forms of cancer therapy. Indeed, tumor cells that get rid of their double minute chromosomes often have greater difficulty proliferating or become more vulnerable to cancer drugs.

The earliest report Wahl has seen that mentions double minute chromosomes was published in the 1960s. "Cytogeneticists have observed these things in cancer cells for years," he says.

The minichromosomes are thought to result from the general genetic instability of dividing cancer cells. As chromosomes fragment, the pieces either reintegrate into other chromosomes or form independent rings.

While scientists have long observed such isolated chromosomal fragments, it wasn't until 1979 that they realized the pieces contain copies of genes, not just meaningless DNA. That year, a research group reported that tumor cells which resist the chemotherapeutic drug methotrexate harbor double minute chromosomes composed of many copies of the gene that encodes dihydrofolate reductase, an enzyme that deactivates the drug (SN: 1/3/87, p. 12).

Since then, investigators have identified many other genes that can appear in the circular DNA fragments. Several of these genes endow tumor cells with greater resistance to chemotherapeutic drugs, while others are oncogenes, mutated genes that encourage a cell's proliferation or growth.

Although double minute chromosomes probably can form with all sorts of genes, those that do not offer the cell some advantage would disappear in time. Unlike normal chromosomes, double minute chromosomes do not have centromeres, the DNA sequences that a dividing cell uses to ensure that its progeny receive an equal number of chromosomes. Consequently, the dozens to hundreds of double minute chromosomes split unevenly between a dividing cell's two progeny.

"One cell is going to get more than the other does," says cytogeneticist Jerome L. McCombs of the University of Texas Medical Branch in Galveston. …

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