Biology Reference
In-Depth Information
MGMT INHIBITION: FIRST FORAY INTO
DNA REPAIR INHIBITION
Low MGMT activity may indicate intrinsic drug
sensitivity in certain cancers (although findings to
date are conflicting).
14
Effects beyond MGMT itself may affect tumor
susceptibility,
9
which alludes to pathway cross-talk.
The first effort to tap into the clinical importance of
understanding DNA repair processes with respect to
cancers came to light when the first nitrosourea was
introduced in the early 1970s as a treatment for glioblas-
tomas and other malignant gliomas.
9
Nitrosoureas are highly lipid-soluble, enabling them
to cross the blood
e
brain barrier to reach gliomas. As
a polyfunctional alkylating agent, nitrosourea achieves
its therapeutic effect by alkylating DNA at various posi-
tions of guanine
e
particularly N
7
, and, to a lesser extent,
O
6
and O
4
.
10
These adducts subsequently cause single- or
double-strand damage (the latter by crosslinking).
11
Early studies, such as one described in a 1975 article
explaining the mechanisms of action of BCNU (1,3-bis
[2-chloroethyl]-1-nitrosourea) and related nitrosoureas,
trumpeted this drug class's “highly selective” anti-tumor
activity.
12
However, scientists soon learned that some-
thing could reverse the DNA damage that those alkylat-
ing agents inflicted on tumors. That something was O
6
-
methylguanine-DNA methyltransferase (MGMT),
a DNA repair protein that removes alkyl groups in
a single-step “suicide” reaction.
13
Thus, the end of the
1970s heralded the first attempts to study DNA repair
pathways in depth for their potential clinical influence.
2
MGMT presented investigators with a unique oppor-
tunity in early studies of DNA repair because this
protein has a restricted mechanism of direct action.
10
MGMT removes only alkyl groups at only the O
6
posi-
tion of guanine, transferring them from the oxygen of
the amino acid to MGMT in a stoichiometric reaction
that subsequently causes ubiquitination and degrada-
tion of MGMT. This requires cells to continually manu-
facture more MGMT to help maintain DNA integrity.
13
More than 20 years of studying
MGMT
10
has made it
the most widely studied gene that encodes a DNA repair
protein.
13
Those studies have revealed many aspects of
DNA repair in general, which continue to be translated
into clinical applications today. MGMT is not critical for
survival, but its pleiotropic effects make it an important
linchpin in the overall scheme of DNA repair. As such,
MGMT possesses many characteristics worthy of study:
13
MGMT interacts with other DNA repair pathways to
help maintain the genome.
15
MGMT activity is somewhat inducible (although this
is transient).
10
MGMTwas successfully inhibited more than 10 years
ago, and that success shed light on how manipulation of
a DNA repair pathway could be used clinically. This
constituted an important “first,” as MGMT was the first
entity studied for DNA repair inhibition.
15
Methylating
the promoter of the gene that encodes
MGMT
inhibits
the cells' ability to make more MGMT, eliminating one
avenue that cells have for repairing DNA damage
caused by alkylating chemotherapeutics such as TMZ,
BCNU, and ACNU.
Based on this knowledge, O
6
-BG (O
6
-benzylguanine)
was identified in 1990 as a potent inhibitor of MGMT.
This was a “first” as well because (1) it was the first
anticancer drug developed as a chemosensitizer and (2)
it was developed on the basis of a target
effect
rather than
on a maximally tolerated dose.
10,16
Clinical trials are
ongoing in this arena to determine to what extent that
MGMT inhibition can increase treatment responsiveness
when alkylating chemotherapeutics are administered.
10
Another potential application stemming from
MGMT
research is gene therapy for myeloprotection. Myeloa-
blation is the most common toxicity that keeps anti-
cancer treatments from reaching truly therapeutic
levels. Because
MGMT
is a potent drug-resistance
gene, its induced overexpression in bone marrow stem
cells prior to chemotherapy can transduce drug resis-
tance and protect against myelosuppression of healthy
cells
e
thus overcoming dose-limiting toxicities while
sparing healthy cells.
10
This represented another “first”: MGMT was the first
molecule targeted as both an inhibitor and a bone
marrow protectant.
Although an MGMT inhibitor was
not
the first DNA
inhibitor to make it out of clinical trials, the ongoing
study of MGMT continues to reveal more information
about DNA repair pathways, their cross-talk and over-
lapping functions. For example, although MGMT
repairs only one lesion that comprises a very small
portion of all DNA methyl adducts, MGMT activity or
lack of activity can have many different effects on
tumor cells, including repair, clastogenicity, mutage-
nicity, or apoptosis
e
all based on interactions with
otherrepairpathways(
Tabl e 1 .2
).
The study of MGMT inhibition is the earliest example
of how a DNA inhibitor was initially considered for
It protects normal cells from naturally occurring
alkylating agents, contributing to genome stability
e
which also diminishes the effectiveness of alkylating
chemotherapeutics.
10
Loss of MGMT activity increases the risk of
carcinogenesis.
10
MGMT levels are altered in many cancers,
10,13
which
can give us insight into malignant transformation and
may provide a potential biomarker for early tumor
detection.
10
