HERSHEY, PennsylvaniaA phase II study is about to begin testing
a novel approach to enhancing the effectiveness of chemotherapy, one
that uses a new agent to deactivate a critical DNA repair mechanism
in malignant cells. Shutting down this repair system appears to
increase the killing power of currently available drugs that work by
What were trying to do is breathe some new life into some
relatively old agents while we wait for new agents that are being
designed based on the molecular biology of cancer, said Anthony
E. Pegg, PhD, of Pennsylvania State University. Dr. Peggs
research provided the rationale for the study and the agent to be
used in the phase II studies.
The trial will be carried out at Case Western Reserve University, the
University of Chicago, and Duke University. The study follows a
successful phase I trial at the same three universities.
Dr. Pegg, professor of cellular and molecular biology at Penn
States Hershey Medical Center, described the innovative effort
at the Council for the Advancement of Science Writing annual seminar.
A number of DNA repair mechanisms exist to deal with damage caused by
natural breaks in the DNA chain, radiation, and exogenous chemicals.
Several of these pathways are quite general, while others are very
specific, which is the case with the mechanism that Dr. Pegg and his
colleagues elucidated. This specific pathway repairs adducts that
occur in a small methyl group found within the DNAs helical
The pathway is a unique reaction, which is brought about by a
protein I call AGT [O6-alkylguanine-DNA
alkyltrans-ferase], which repairs this DNA, Dr. Pegg said. In
the absence of this repair mechanism, some tumor cells express what
is called the mer phenotype. Such cells are very susceptible to
certain cancer drugs, such as DNA methylating agents and DNA
crosslinking agents. These drugs include carmustine (BCNU), lomustine
(CeeNu), and dacarbazine.
If you treat these tumors with these agents, they work very
well, Dr. Pegg said. Unfortunately, very few primary
tumors lack this repair protein, so most tumors are inherently resistant.
He and his colleagues set out to develop an inhibitor of AGT that
would convert mer+ tumor cells to mer cells so that
the cancer drugs would be more generally useful. They
named their inhibitor O6-benzyl-guanine. In the phase I
clinical trials, researchers found that following an hour-long
infusion of O6-benzylguanine, the repair mechanism
activity is lost completely and remains low for 20 hours or
so, Dr. Pegg said. This is really quite encouraging.
The inhibitor breaks down quickly into an active metabolite (O6-benzyl-8-oxoguanine),
which appears in much larger amounts than the original agent
and is as good an inhibitor as the parent drug was, he added.
Phase I data indicate that doses of the inhibiting agent up to 100
mg/m², a dose that completely inactivates the AGT protein, can
be given safely.
It doesnt appear that inactivating this repair process,
in this situation, has any toxicity on its own, Dr. Pegg said.
However, when you combine the inhibitor with the agent BCNU,
the myelosup-pression induced by BCNU is enhanced. The dose-limiting
toxicity of these agents is myelosuppression. As a result, the
dose of BCNU given to patients is approximately one quarter of
that used in the current therapeutic regimens.
Only further testing will reveal whether O6- benzylguanine is a
sufficiently potent inhibitor to be clinically useful. We think
it is, but there is certainly plenty of opportunity to make a
compound that is more active or that could be given more easily,
Dr. Pegg said.
He also questioned whether the targeted repair mechanism is the only
one in tumor cells that can confer resistance to chemotherapy.
It is very hard to kill tumor cells selectively, and I think it
is very unlikely that there arent other means of resistance to
these agents, he said. But the key point is that this DNA
repair protein is absolutely a primary means of resistance. If you
dont knock this DNA repair program out, you will never be able
to exploit the full potential of these chemotherapy agents.