Biology Reference
In-Depth Information
BG + alkylating
agents or methylating
Agents treatments
Gene-modified HSCs
BG +
BCNU or TMZ
MGMT-P140K &
therapeutic gene
transfer vector
WT MGMT
MGMT-P140K
Therapeutic protein
FIGURE 2.4
MGMT-P140K mediated in vivo selection. After infusion of transduced heterogeneous population of HSCs, transduced HSCs
containing MGMT-P140K can be enriched in vivo by treating patient with BG and BCNU or TMZ. Untransduced cells will die due to DNA
damage caused by BG and BCNU or TMZ treatment, and transduced cells with MGMT-P140K are protected and will survive. A therapeutic gene
can also be inserted together with MGMT-P140K and it can express a therapeutic protein with MGMT-P140K.
FIGURE 3.5
Differential effects of BER inhibi-
tors in normal and tumor cells based on their
BRCA (breast cancer type I susceptibility protein)
status. The non-tumor cells would have functional
BER and two copies of BRCA proteins and be
competent to repair their DNA. Tumor cells have
acquired a mutation in BRCA proteins which
diminishes their DNA repair capacity but the other
DNA repair pathways are able to compensate and
the tumor survives. When these BRCA-deficient
tumor cells are challenged with a BER inhibitor
their capacity for DNA repair is severly compro-
mised and they are unable to survive. This idea
that it takes two hits to kill the tumor cell is
referred to as synthetic lethality. Clinical trials in
a patient population enriched for BRCA deficiency
with PARP inhibitors are showing clincal success.
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