Chemistry Reference
In-Depth Information
time the repair process will fail and a cell will enter one of the following states: (i)
apoptosis or cellular suicide and necrosis; these are processes by which the cell destroys
itself; (ii) senescence, a process whereby the cell becomes irreversibly dormant; (iii)
uncontrolled cellular division; this can result in tumour formation and cancer.
Thus, DNA repair has a signifi cant role in modulating cytotoxicity of platinum
drugs. The interruption of pathways that are involved in repairing platinated DNA
represents a powerful approach to cancer treatment. It is therefore not surprising
that repair of damage to DNA induced by platinum antitumour drugs and its down-
stream effects in tumour cells is, at present, a very active area of molecular
pharmacology.
The purpose of this review is to highlight recent discoveries related to repair
of DNA damage induced by anticancer platinum drugs. The topics discussed do not
involve mechanisms underlying repair of DNA damage by platinum compounds in
bacterial or yeast systems.
6.2 Human DNA Repair Systems
All macromolecules in a living cell, i.e., nucleic acids, proteins, lipids and carbohy-
drates can be damaged when the cells are exposed to deleterious agents, including
antitumour metal-based drugs. A major defence against damage to cells is DNA
repair. Although other biomacromolecules may be damaged and subject to repair,
the signifi cance and exceptionality of DNA repair in cellular processes is accentu-
ated by the fact that only failure to repair DNA damage has fatal consequences for
the cells. If other cellular molecules are damaged, they can be degraded and newly
synthesized via transcription and translation. Thus, for instance, damage to cellular
proteins is usually not corrected since, due to the large number of different chemical
modifi cations, it seems to be chemically and evolutionally impossible to develop the
required set of enzymes to correct damage to proteins. Therefore, very often protein
degradation is the only way to remove such damaged proteins from the protein pool.
Ribozyme mediated strategies exist that can be used to amend damaged genetic
instructions at the RNA level.
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An obvious limitation of RNA repair is, however,
the fact that repair of RNA only results in transient production of corrected genetic
instructions, as the damaged DNA template is not amended. DNA repair, which is
present in all organisms examined, including bacteria, yeast, drosophila, fi sh, amphib-
ians, rodents and humans, is involved in processes that minimize cell death, muta-
tions, replication errors, persistence of DNA damage and genomic instability. All
organisms must keep their DNA intact and free of lesions to obtain faithful trans-
mission of genetic information. There are several different DNA repair pathways
in mammalian cells, as described in the sections 6.2.1-6.2.4.
6.2.1 Direct Reversal of Damage
This type of DNA repair is relatively rare and involves chemical reversal of damage.
It does not involve breakage of the phosphodiester backbone and is specifi c to the
