How does hydroxyurea, at concentrations much lower than those given to cancer patients, eliminate double minute chromosomes from laboratory-grown cells?
In the absence of a chemotherapy drug, double minute chromosomes containing resistance genes are a burden to cancer cells grown in a test tube, notes Snapka, now at Ohio State University in Columbus.
Hydroxyurea, Snapka contends, somehow exaggerates the growth disadvantage of cells with double minute chromosomes.
Wahl has been pursuing a different explanation for hydroxyurea's skill at eliminating double minute chromosomes. His research indicates that cells can actively discard these fragments and that hydroxyurea, as well as related drugs, encourages that shedding of DNA.
In the March 23 Journal of Cell Biology, Wahl, Noriaki Shimizu of Hiroshima University in Japan, and their colleagues report that the removal of double minute chromosomes occurs through a novel variation of a process called micronucleation.
Wahl's group has found that double minute chromosomes are incorporated into micronuclei but that the process occurs inside the cell's nucleus.
Wahl and his colleagues have recently developed a colorful new tool that allows them to look at double minute chromosomes in living cancer cells.
You can even see little chromosome fragments, such as double minute chromosomes," says Wahl.
Although the investigators believe that the histone-GFP protein offers an excellent way to study overall chromosomal dynamics, including how DNA moves in a dividing cell, they have concentrated their initial efforts on double minute chromosomes. In a study reported in the March 26 Current Biology, the histone-GFP method revealed that some of the minichromosomes hitchhike on full-sized chromosomes as they segregate in dividing cells.
The investigators hope eventually to use the histone-GFP protein, and their new understanding of how cells oust double minute chromosomes, to design a test of how effectively various compounds spur the elimination of the DNA loops.
"Here's an approach for therapy where you don't care what the gene is, you don't care what is encoded by the double minute chromosomes, you just know that whatever is encoded is important for cancer progression," explains Wahl.