[ RadSafe ] Lithium May Help Radiation Target Cancer, Spare Healthy Tissue

[Cary Renquist]

They found that lithium did not prevent the generation of DSBs but
promoted a particular kind of DNA repair - called nonhomologous
end-joining (NHEJ) repair - which is the predominant repair mechanism
used by normal neurons. Xia and colleagues showed biochemical and
genetic evidence that radiation-induced DSBs were repaired with greater
efficiency in lithium-treated cells via the NHEJ pathway.

However, none of these effects were observed in malignant glioma (brain
tumor) cells, presumably because cancer cells generally utilize a
different DNA repair mechanism, Xia said.

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Lithium May Help Radiation Target Cancer, Spare Healthy Tissue -
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Lithium May Help Radiation Target Cancer, Spare Healthy Tissue

May 2009

Vanderbilt-Ingram Cancer Center investigators have uncovered a mechanism
that helps explain how lithium, a drug widely used to treat bipolar mood
disorder, also protects the brain from damage that occurs during
radiation treatments.

In the May 1 issue of the Journal of Clinical Investigation, Fen Xia,
MD, PhD, and colleagues show that lithium promotes DNA repair in healthy
cells but not in brain tumor cells. The findings suggest that lithium
treatment could offer a way to protect healthy brain tissue from damage
that may occur during cranial radiation treatments.

Cranial irradiation is part of standard therapy for both primary and
metastatic brain tumors. However, as with all treatment modalities,
radiation often causes long-term side effects. In particular,
neurological impairments - including lowered IQ, learning difficulties
and memory loss - have been reported, especially in children treated for
brain cancers. Radiation-induced damage to the healthy cells of the
hippocampus, a brain structure crucial for learning and memory, is one
likely source of these deficits.

These cognitive impairments have long-lasting effects on the quality of
life for survivors, noted Xia, an assistant professor of Radiation
Oncology and Cancer Biology.

"Because these patients can now survive longer and are being cured,
alleviating long-term toxicity is becoming more important," she said.

Researchers have been searching for agents that could protect healthy
brain tissue from radiation-induced damage. Previously,
Vanderbilt-Ingram investigators - led by Dennis Hallahan, MD, chair of
Radiation Oncology and the Ingram Professor of Cancer Research - found
that lithium treatment protects cultured hippocampal neurons from
radiation-induced cell death and improves cognitive performance in
irradiated mice.

But how lithium protects against radiation-induced damage is unclear.

Radiation kills tumor cells by damaging their DNA, but it can also
attack the DNA of healthy cells. One of the most serious types of DNA
damage is the chromosomal double-stranded break (DSB), in which both
strands of the double helix are severed. Even a single unrepaired DSB
can be lethal to a cell. Fortunately, the body has several different
ways to repair DNA damage.

Xia, whose lab studies the mechanisms of DNA repair in normal cells and
tumor cells, suspected that lithium might affect how DNA is repaired
following radiation-induced damage.

Working with Eddy Yang, MD, PhD, a resident in the Radiation Oncology
department and an American Board of Radiology Holman Research Scholar,
and postdoctoral research fellow Hong Wang, MD, PhD, Xia and colleagues
examined DNA repair in lithium-treated mouse hippocampal neurons exposed
to radiation.

They found that lithium did not prevent the generation of DSBs but
promoted a particular kind of DNA repair - called nonhomologous
end-joining (NHEJ) repair - which is the predominant repair mechanism
used by normal neurons. Xia and colleagues showed biochemical and
genetic evidence that radiation-induced DSBs were repaired with greater
efficiency in lithium-treated cells via the NHEJ pathway.

However, none of these effects were observed in malignant glioma (brain
tumor) cells, presumably because cancer cells generally utilize a
different DNA repair mechanism, Xia said.

The researchers confirmed these findings in mice treated with cranial
radiation. The results suggest that lithium protects healthy hippocampal
neurons by promoting NHEJ-mediated DNA repair - but that lithium offers
no protective effect in the brain tumor cells tested.

Since some tumors are resistant to radiation, Xia hopes that lithium
treatment could provide a way to increase the radiation dose to levels
that will kill the tumor cells while protecting healthy brain tissue.
The team is launching an investigation of the safety and feasibility of
lithium treatment in patients with low-grade glioma or brain metastases
from small cell lung cancer.

Release date: May 1, 2009

Source: Vanderbilt-Ingram Cancer Center