[MOL] Re: New Mitosis Checkpoint Gene Linked To Cancer [01788] Medicine On Line

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[MOL] Re: New Mitosis Checkpoint Gene Linked To Cancer

> New Mitosis Checkpoint Gene Linked To Cancer
> In health, most cells undergo a carefully orchestrated cell division
process in order to replicate. At the heart of this process is mitosis, in
which a cell's nucleus duplicates its genetic material and divides.
> Precisely controlled mitosis is vital to survival, and rigorous checkpoint
mechanisms are in place to ensure that each step in the process is properly
executed before the cell moves on to the next step.
> Although not well proven, it is generally believed that many human cancers
stem from checkpoint defects in mitosis.
> In the July 27 issue of Nature, scientists at the Wistar Institute report
identification of a new gene called chfr that establishes a previously
unknown checkpoint in mitosis.
> Further, a laboratory survey of eight human cancer cell lines found chfr
to be inactivated, through lack of expression or mutation, in four of the
eight -- fully half of the cell lines studied.
> Mitotic checkpoint genes identified in earlier studies had been linked to
cancers, too, but mutant versions had been found in only 1 or 2 percent of
> "The frequency of mutations in previously identified mitotic checkpoint
genes is too low to explain the incidence rates of cancers in which troubled
cell division is thought to play a role," says Thanos D. Halazonetis,
D.D.S., Ph.D., senior author on the study and an associate professor at
> "So," he adds, "the question was whether there were checkpoint genes we
didn't know about and whether those were the genes suffering mutations in
these cancers.
> "What we found was a new gene and a wholly new mechanism that monitors
progress through mitosis. Further, this gene was disrupted in 50 percent of
the cancer cell lines we studied, much higher than the rates for other known
checkpoint genes."
> Halazonetis emphasizes that studies of tumors from patients will be needed
to confirm that mutant chfr is as common in primary cancer cells as it is in
laboratory cancer cell lines. If the findings are confirmed, however,
clinical applications immediately suggest themselves, according to
Halazonetis, as do new avenues for drug development.
> "Patients whose cancers exhibit chfr defects would be likely to respond
well to TaxolŽ or other drugs that act by interfering with mitosis," he
says. "Those cancers would be unusually sensitive to drugs in this class.
So, a diagnostic test for inactivated chfr might be used to predict the
responsiveness of a patient's cancer to TaxolŽ or a related drug, allowing
doctors to give their best drug at the start of therapy.
> "Our findings could also be useful in developing new drugs that might be
more effective than TaxolŽ or more specific in targeting only cancer cells,
which would lead to reduced toxicity."
> Broadly put, mitosis has four phases -- prophase, metaphase, anaphase, and
telophase -- in which the chromosomes replicate and condense, align,
separate, and then regroup in an orderly way prior to the division of a
parental cell into two daughter cells.
> The process is largely guided by physical structures known as
microtubules. TaxolŽ and drugs in its class act by interfering with the
formation of microtubules.
> For the current study, Halazonetis used several compounds, including
TaxolŽ, to induce defects in mitosis and then observed the outcomes in cells
with or without functional chfr.
> Normal cells and cancer cells with a working chfr checkpoint stopped
mitosis during prophase, preventing entry into metaphase until such time as
prophase could be properly executed. Cancer cells without a functional chfr
checkpoint, however, continued to complete the entire process of mitosis
despite serious defects and died.
> Prior to the current study, the known mitotic checkpoints monitored the
proper completion of metaphase before allowing the process to proceed to
anaphase. The newly identified chfr gene is the first identified that
monitors prophase.
> TaxolŽ is the brand name for the drug paclitaxel; TaxotereŽ is the brand
name for another well-known drug in this class, docetaxel. A fact sheet on
these drugs is available atthis website.
> With senior author Halazonetis, the lead author on the two-author study is
Daniel M. Scolnick, Ph.D.
> Support for the Halazonetis laboratory is provided by the American Cancer
Society, the Department of Defense, and the National Cancer Institute, one
of the National Institutes of Health.
> The Wistar Institute is an independent nonprofit biomedical research
institution dedicated to discovering the basic mechanisms underlying major
diseases, including cancer and AIDS, and to developing fundamentally new
strategies to prevent or treat them.
> The Institute is a National Cancer Institute-designated Cancer Center --
one of the nation's first, funded continuously since 1968, and one of only
ten focused on basic research.
> Founded in 1892, Wistar was the first institution of its kind devoted to
medical research and training in the nation. - By Franklin Hoke

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