Biomedical Engineering Reference
In-Depth Information
effect on the activation of HIF-1α [56]. Because of the interference in
DNA repair, the upregulation of autophagy, and the downregulation
of NF-
B and HIF-1α, PARP inhibitors are potentially strategic
modalities for potentiating the tumor cell death from administration
of cytotoxic therapy. Recent data suggest PARP inhibitors may trap
PARP 1 and 2 leading to cytotoxicity that is independent to the
inactivation of PARP [57a].
PARP inhibitors currently under development include
AstraZeneca's olaparib (AZD2281, KU-0059436), Abbott
Laboratories' veliparib (ABT 888), Clovis's rucaparib (AG014699,
PF 1367338), Tesaro's niraparib (MK 1827) Cephalon's CEP 9722,
and Biomarin's BMN673 (LT-673). Sanofi/BiPar's iniparib (BSI
201), which had shown initial activity in TNBC [76], was recently
reported not to inhibit PARP [78]. Its mechanism of action is under
investigation. Unfortunately, like with other forms of cancer therapy,
there appears to be development of resistance to PARP inhibitors.
κ
15.4
PARP Inhibitors as Single Agents to Induce
Synthetic Lethality in
BRCA
Tumor Cells
The combination of agents that bring about cell death when neither
alone would do so is termed synthetic lethality [8,9]. This technique
has been exploited by treating tumors expressing
BRCA
mutations
with PARP inhibitors [57]. Cells with mutated
, resulting in
defective HR repair, are more dependent on other pathways for DNA
repair, utilizing BER. If BER is inhibited by a PARP inhibitor, DNA
repair cannot occur by either BER or HR. If SSBs cannot be repaired
because of defective BER, such as with the use of PARP inhibitors,
SSBs result in collapsed replication forks that ultimately result in the
formation of DSBs. Typically, DSBs would be repaired via the error
free HR pathway; however, in the presence of homozygous mutations
in the
BRCA
genes in the tumor, HR is ineffective. Cell death, or
apoptosis, and error-prone recombination through the NHEJ
pathway result. This phenomenon is thought to occur preferentially
in the tumor cells as the normal cells are heterozygous for the BRCA
gene and thus retain HR function, while tumor cells are homozygous
for the mutation making them HR defective [8, 14,15, 26, 58].
PARP inhibitors, as single agents, kill BRCA2 deficient cells at
doses that are not toxic to normal cells both
BRCA
in vitro
and in xenograft
