Chemistry Reference
In-Depth Information
6
Role of DNA Repair in Antitumour
Effects of Platinum Drugs
Viktor Brabec and Jana Ka š p á rkov á
6.1 Introduction
Understanding the molecular and biochemical mechanisms associated with the
biological effects of the existing platinum agents provides important insights for
designing new and more effi cient platinum-based drugs. There is a large body of
experimental evidence suggesting that the success of platinum complexes in killing
tumour cells results from their ability to damage DNA by forming various types of
covalent adducts.
1 - 4
Hence the research into DNA interactions with platinum anti-
tumour drugs has predominated.
5,6
However, cells have developed effi cient tools to
correct any chemical changes in DNA so that the genetic information is retained
uncorrupted.
Agents that damage DNA involve: (i) ionizing and ultraviolet radiation; (ii)
highly reactive oxygen radicals produced during normal cellular respiration, as well
as by other biochemical pathways; (iii) chemicals in the environment, such as various
hydrocarbons, including some found in cigarette smoke, some plant, fungal and micro-
bial products, e.g. the afl atoxins produced in mouldy peanuts and not least (iv) chemicals
used in chemotherapy, especially in chemotherapy of cancer (see Table 6.1).
Major types of DNA damage are: (i) all four of the bases in DNA (A, T, C, G)
which can be covalently modifi ed at various positions. One of the most frequent is
the loss of an amino group ('deamination') resulting, for example, in a C being
