Chemistry Reference
In-Depth Information
5
Platinum Drugs, Nucleotides
and DNA: The Role of
Interligand Interactions
Giovanni Natile and Francesco Cannito
5.1 Introduction
Cisplatin,
cis
- diamminedichloridoplatinum(II), was the fi rst inorganic antitumour
drug used in clinics
1
and, after more than 30 years, remains one of the most widely
used and successful drugs in cancer therapy.
2,3
Today cisplatin is routinely used, alone or in combination with other anticancer
drugs, for the treatment of lung, ovary, testes and bladder cancers
4
and shows activity
against slow-growing as well as rapidly growing tumours. However, as with all
chemotherapeutic drugs, cisplatin also has drawbacks, including intrinsic or acquired
resistance and toxicity. Toxicity and resistance both have a negative infl uence on the
cure rate.
5,6
Some of the severe safety issues have been solved by the introduction of car-
boplatin, which is equally effective as cisplatin, but with a more acceptable side-
effect profi le (Figure 5.1 ).
A key development, in more recent years, has been the elucidation of the
mechanism of tumour resistance to cisplatin which includes decreased membrane
transport of the drug,
7,8
increased cytoplasmic detoxifi cation,
9,10
increased DNA
repair,
11 - 13
and increased tolerance to DNA damage.
14 - 16
The efforts to circumvent the mechanisms of resistance and thereby broaden
the clinical utility of this class of agents have resulted in the discovery of oxaliplatin
