Introduction - Free-Radical-Induced DNA Damage and Its Repair - page 3

A number of anticancer drugs that kill cells by destroying their DNA via free
radicals are used in the clinic. They show a most remarkable chemistry. Some of
it is fairly well understood. Where important open questions remain, attention
is drawn to these in order to elicit future studies that are urgently needed for a
better understanding of the underlying mechanistic principles.
Free-radical-induced reproductive cell death is the basis of radiotherapy, and
it is obvious that the main problem of this approach to fight cancer is to target
the ionizing radiation to the tumor in order to prevent damage to healthy tissue.
This is a most difficult if not impossible task. Radiation modifiers that sensitize
the tumor cells and protect healthy tissue are considered for improving treat-
ment regimes in radiotherapy, and the underlying mechanistic principles are
addressed.
Free radicals, notably the superoxide radical, are by-products of the cellular
metabolism and transition-metal ions seem to play a role in causing DNA dam-
age in vivo. This may lead to mutations and eventually to cancer, and some of
the phenomena of aging have also been attributed to free-radical-induced DNA
damage. We are still far from understanding these reactions in sufficient de-
tail, but the reader will find chapters on peroxyl radical chemistry and on some
aspects of the involvement of transition-metal ions in free-radical reactions on
which future work may be based.
Cells have two defense systems to cope with free-radical DNA damage that
work on very different time scales: the fast 'chemical repair' by thiols that oc-
curs at the stage of DNA free-radicals and the slow enzymatic repair that only
sets in once the damage is fully set. The present topic deals in some detail with
the chemical repair. To discuss the even more important enzymatic repair would
have exceeded the space allocated to this topic, and enzymatic repair is only
brief ly touched on.
It is impossible in a topic of a scope as wide as the present one to refer to all
studies that may be relevant to a certain topic, but the many references that are
given here will allow the reader to find an entry into the wider literature.
In science, there is a hierarchy of questions: (i) 'what', (ii) 'how', and (iii)
'why'. The report of a given fact, e.g., the determination of a series of products
and their yields, only answers the question 'what'. Additional kinetic studies
raise our level of understanding, as it answers the question 'how'. The ulti-
mate scientific question, 'why', has as yet rarely been answered, but this level of
knowledge is a prerequisite for being able to predict a certain reaction without
too many f flanking experiments. Thus, it will be one of the main goals of future
research to strive for an in-depth theoretical understanding. This, of course, has
to be based on our present (and future) experimental data, and it is one of the
intentions of this topic to provide the necessary information in a compact form.
DNA research is a very multidisciplinary field, with contributions by biolo-
gists, biochemists, chemists, physicists and theoreticians. Hence, the presen-
tation given here should be at a level that it can be understood even when the
educational background is not chemistry. In parts, this goal may not have been
fully reached, but at other instances it may have led to some oversimplifications.
I ask for apologies. Yet, in the 1920s, nuclear physicists enjoyed discussing that
Wahrheit and Klarheit (truth and clarity) may be a conjugate pair connected in a