Biology Reference
In-Depth Information
anti-hypertensive drug, hydralazine.
184
Potentially these
data are very interesting suggesting that AG014699 at
least and potentially other PARPi may not only improve
the delivery of drugs to tumors but also improve tumor
oxygenation thus reducing the radio-resistant hypoxic
fraction. Furthermore, since hypoxia induces HIF1
a
,
which promotes the malignant phenotype and angiogen-
esis, PARPi may ameliorate some of these undesirable
characteristics.
The other reason that PARPi may be beneficial in
combination with drugs for which there seems to be
little scientific rationale is the potential for normal tissue
protection. In normal quiescent tissues the need to repair
DNA damage rapidly before it is fixed by replication is
not as vital as in proliferating tissues. In these quiescent
tissues reactive oxygen species (ROS) can exert their
cytotoxicity by activating PARP-1, leading to cata-
strophic NAD depletion and the triggering of AIF
release from mitochondria by the ADP-ribose polymers,
setting off the process of caspase-independent
apoptosis. There is abundant evidence for the protective
effects of PARPi against a variety of insults:
will require further evaluation and validation within
prospective clinical trials before they can be adopted as
predictive tools directing treatment decisions in patients.
VASCULAR EFFECTS AND
PROTECTION OF NORMAL TISSUE
TOXICITY
The first inhibitor to enter phase III trials is iniparib
(BSI-201, 4-iodo-3-nitrobenzamide). This inhibitor
demonstrated excellent clinical activity in combination
with carboplatin and gemcitabine without increased
toxicity as described above. However, as previously dis-
cussed, this inhibitor has a different MoA compared to
the other inhibitors in that it irreversibly binds PARP-
1, preventing it binding to DNA, and also covalently
reacts with other cellular proteins. The sagacity of using
this drug as a model for the clinical evaluation of other
PARPi, particularly in the absence of supporting precli-
nial data, is therefore questionable. However, there are
two potential reasons why the combination of PARPi
with drugs for which there is no apparent scientific
rationale might work: the potential vasoactivity of
PARPi leading to greater drug delivery and the protec-
tive effect of PARPi in quiescent normal tissues.
Early studies with nicotinamide revealed that it had
significant vasoactivity, causing profound hypotension
and altering the PK of administered cytotoxic drugs.
182
This observation has been exploited clinically where
nicotinamide is used to increase tumor perfusion and
oxygenation to improve radiotherapy response.
183
Administration of the next generation PARPi, PD128763
to mice also resulted in hypothermia and hypotension.
55
This compound caused hypothermia to a similar extent
and duration in PARP-1
þ
/
þ
and PARP-1
-/-
mice, but
parallel studies with AG014361 did not cause hypo-
thermia in any mice, suggesting that the effect was not
PARP-1 mediated.
79
Nevertheless, AG014361 did have
a marked and immediate effect on the tumor vasculature.
In general, tumors are poorly and erratically perfused
due to a combination of the deranged vasculature and
high interstitial pressure within the tumor. This leads to
blood vessels periodically failing and the blood supply
to some areas of the tumor shutting down intermittently.
Both AG014361 and AG014699 reduced the number of
blood vessels shutting down and improved drug flow
in animal models. Visualization of this effect was made
using fluorescent dyes, administered 20 minutes apart
to mark blood vessels that were open at the time of injec-
tion and direct measurement of the diffusion of fluores-
cent labels in a dorsal window chamber.
79,184
A direct
effect on the relaxation of blood vessels was demon-
strated
ische-
mia
reperfusion injury (e.g. stroke and heart attack),
chronic and acute inflammation (e.g. arthritis, asthma,
septic shock, diabetes).
67,68
Pertinent to anticancer
chemotherapy are the dose-limiting cardiotoxicity of
doxorubicin and the renal toxicity of cisplatin, both of
which are thought to be due to radical formation rather
than the same mechanism by which their anticancer
activity is achieved. There is evidence that doxoru-
bicin-induced cardiotoxicity is due to PARP hyperacti-
vation and it can be ameliorated by PARP
inhibition.
185,186
Similarly, Both 3AB and the PARP
inhibitor, BGP-15, have a protective effect on cisplatin-
induced kidney damage.
116,187
e
SUMM
ARY AND FUTURE DIREC
TIONS
Over the past 40 years the scientific understanding of
the processes of DNA damage and repair has advanced
in many spheres, possible none more so in the study of
poly(ADP-ribose) polymerase. The wealth of scientific
knowledge has allowed the clinical development of
a whole new class of anticancer compounds to take place
in a rapid time frame for drug development.
A very exciting class of DNA damage response
modulators has, therefore, entered the clinic in the last
decade and there would appear to be significant poten-
tial for clinical benefit fromuse as single agents in appro-
priately selected populations of patients, and also in
combination with other chemotherapeutic drugs. The
challenge remains to be able to appropriately identify
patients where their tumor carries an HR defect and is
vulnerable to synthetic lethality when treated with
using
pre-constricted
rat
arteries, with
AG014699 being more potent
than the
common
