LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
to high LET radiation. Such genome loss will contribute to genome instability of the
tumor cells, and a probable final outcome is cell death. High LET-induced non-DSB
clusters containing opposing AP sites would be particularly toxic via the formation of
DSBs which will be poorly repaired, or due to the presence of unrepaired AP sites. A
dead cell is a good cell not only for tumor eradication, but also for normal tissue since it
prevents replication of damaged cells with radiation-induced mutations. With respect to
the biological effectiveness of clustered DNA damage, high LET radiotherapy seems to
present a relatively better benefit over risk to the patient than low LET radiotherapy.
Indeed, in combination with a low dose deposited in the entrance channel, fewer as well
as more easily repairable damages are produced in normal tissue, whereas a large dose is
deposited in the tumor, accompanied by complex and poorly repairable lesion production.
In addition, our understanding of repair processes at clustered lesions lets us predict that
inhibiting the late steps of BER should increase toxic DSBs and repair intermediates and
consequently would be beneficial for tumor cell killing and a combination of inhibitors
for the late steps of BER, HR and/or NHEJ would lead to additional cell killing.
Many studies on signaling pathways after low and high LET radiations have found the
activation to be similar except in the intensity [214] but since the end result is different,
there must be a divergence of pathways at some stage.
Since the production of ROS is a major feature of irradiation where some of these could
be permeable, it was of interest to look at the effect of irradiation on cells that had not
exposed to radiation, i.e. the Bystander effect.
74