Cancer drugs affect mouse genomes for generations

Three common chemotherapy drugs cause DNA mutations not only in
mice that receive treatment, but also in their offspring,
according to a study published today in the Proceedings of
the National Academy of Sciences USA1.

The results suggest that the genome in treated mice became
destabilized yielding new mutations long after exposure to the
drugs has ceased. A similar phenomenon has been observed in
mice exposed to radiation.

Genomic damage can be seen in the offspring of mice who
have received chemotherapy drugs.

PAUL WOOTTON/SCIENCE PHOTO LIBRARY

The work emphasizes the importance of looking at the effects of
chemotherapy not only on recipients, but also on their
descendants, but Yuri Dubrova, a geneticist at the University
of Leicester, UK, who led the study, cautions against
extrapolating the results of this study to humans. Most
adults treated for cancer are either too old to have children
or become sterile from the treatment. “So we’re talking about
one group only: childhood cancer survivors,” says Dubrova.

One recent study found no significant impact of radiation or
chemotherapy on the rate of birth defects in 4,699 children of
childhood cancer survivors2.

Furthermore, children who are treated for cancer will not have
children of their own for years or decades afterwards. Mice
only live about two years, and the ones in Dubrova’s study
reproduced a few months after their exposure to the drugs.
“I would be very careful in interpreting this data,”
Dubrova says.

Genomic stability

Genome instability has intrigued Dubrova for more than a
decade. Dubrova and his colleagues were studying the effects of
radiation when, purely by chance, they decided to look at
mutation rates in the offspring of exposed mice. “What we found
was the biggest surprise of my life,” he says. The children had
several times more mutations in their eggs and sperm than
their radiation-treated parents3.
“The genomes were unstable, and we still don’t know why,”
Dubrova says.

Since then, he and his team have gone on to look at whether
mutation-causing chemicals produce the same
effects. The effects of chemotherapy
could be more dramatic, the they reasoned, because cancer-free
regions of the body are often shielded from radiation therapy,
but chemotherapies are generally given systemically, and can
affect many tissues of the body, especially those containing
dividing cells where DNA is rapidly replicating.

For the latest study, the researchers looked at the effects of
three common chemotherapies — cyclophosphamide, mitomycin C and
procarbazine, at doses comparable to those used to treat
cancers in people — on a single region in the mouse genome
containing a short, repeated DNA sequence.

Mutations in this region were twice as common in the
offspring of treated males than they were in either parent. And
the mutations appeared in DNA inherited from the exposed father
and the untreated mother alike.

Innocent bystanders

The results are intriguing, says Joe O’Sullivan, a radiation
oncologist at Queen’s University in Belfast, particularly
because the chemotherapies used in Dubrova’s study cause
different forms of DNA damage than ionizing radiation, which
snaps strands of DNA in two, but the two forms of damage have
similar effects.

In recent years, researchers have begun to investigate the
‘bystander effect’, in which cells that do not directly receive
radiation show signs of radiation-induced changes. It’s
possible that some of these effects — perhaps linked to
signalling between cells — could contribute to the heritable
genomic instability seen in response to radiation and, now,
chemotherapy, O’Sullivan notes.

But he also cautions against reading too much into the
implications for humans who receive chemotherapy treatments,
noting that that the few who do go on to have children are
generally asked to wait at least a year after treatment before
doing so. “It’s something we’ve generally advised for a long
time,” he says, “even though we haven’t had much evidence to
back it up.”

See the article here:
Cancer drugs affect mouse genomes for generations