LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

SYNOPSIS
The average energy locally imparted to the medium per unit length of the path
traversed is the Linear Energy Transfer (LET) of the ionising radiation. On this basis
ionising radiation can be classified into high and low LET radiation. High LET radiations
are predominantly causes direct effect whereas low LET radiations are predominantly
causes indirect effect [3, 4]. Direct effects occur when an ionizing particle interacts with a
macromolecule in a cell (DNA, RNA, protein etc.) where as indirect effects involve the
interaction of ionizing radiation with the medium in which the molecules are suspended,
especially water, to produce free radicals and reactive oxygen species (ROS), in presence
of oxygen, that damage critical targets.
Ionising radiation exposure causes a spectrum of lesions within the cell. These
include, at the DNA level, single strand breaks (ssb), double strand breaks (dsb), base
damage, DNA-protein crosslinks etc. Apart from DNA damage, other lesions in cellular
macromolecules (lipids, proteins etc) are also generated. DNA as a target assumes added
importance due to the very limited redundancy of information in the molecule. Any
irreversible damage may lead to loss of genetic information vital for cellular function and
survival. However, the non DNA lesions, probably not as life threatening to the cell, can
stimulate various signaling pathways which determine the final fate of the cell [5].To
complicate matters a number of non-targeted and delayed effects associated with
radiation exposure, referred to as “bystander effect”, may also contribute to mutagenic
events and genome instability in adjacent unexposed cells [6].
The very obvious application of this was the use of ionising radiation as a potent
tool in cancer therapy. This took advantage of inherent radiosensitivity of tumors over
surrounding normal tissue. Moreover, introduction of fractionated radiotherapy by
Coutard was a major step in enhancing the efficacy of radiotherapy [7]. Radiation therapy
has enjoyed tremendous success in the field of cancer, so much so that it is used in the
treatment of two thirds of all cancer patients in India today. However, one of the major
hurdles in the success rate is radioresistance of tumors which may be innate or acquired.
Therefore, study of fractionated irradiation induced signaling in mammalian cells will be
of great importance.
Exposure of cells to ionising radiation leads to the activation of existing cellular
response pathways [8]. These pathways are predominantly either cytoprotective or
cytotoxic. The activation of the former leads to repair, survival and proliferation whereas,
the activation of the latter leads to cell death. Radiation effects are mediated through the
activation of damage sensors which transduce the signal through the signaling cascades.
These in turn direct the response elucidated, depending upon the signaling pathway that is
predominantly activated. Various studies have shown the activation of cytoprotective
factors contribute to radioresistance in the tumors.
Another, albeit less studied, field is high LET radiation induced signal
transduction. This assumes greater importance because of the increased application of
charged particle beam in radiotherapy and the emergence of the phenomenon of radiation
induced bystander effect. The latter is especially relevant in case of low dose exposure to
high LET radiation (e.g. From Radon) where the damage seen in much more than would
be expected by extrapolating from higher doses. It would be of interest to study the effect
of high LET radiation on the signaling pathways since the damage produced by high LET
radiation (clustered damage) is very different from that by low LET (scattered damage)
[9].
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