Chemistry Reference
In-Depth Information
and V, with a brief digression into the important application of paramagnetic metal complexes for magnetic
resonance imaging.
Cisplatin, an Anticancer Drug
Cisplatin, cis-[PtCl
2
(NH
3
)
2
], is extensively used for the treatment of testicular and ovarian cancers and increas-
ingly against other types of solid tumours (head/neck, lung, cervical, and bladder), and gives a greater than 90%
cure rate in the case of testicular cancer. It was first synthesised by Peyrone in 1845 (known as Peyrone's salt), and
its structure was elucidated by Alfred Werner
4
in 1893. In the 1960s, it was rediscovered serendipitously
5
when
Rosenberg et al. investigated the effects of electric fields on bacterial growth. In the presence of NH
4
Cl, Pt
electrodes and sunlight, E. coli cultures grew up to 300 times their normal length but the cells failed to divide.
They found that the electric field was not responsible for the arrest of cell division, but that small amounts of
certain platinum compounds formed during the electrolysis were responsible. Reasoning that if it inhibited cell
division it might be effective as an anticancer drug, they then found that whereas the trans isomer was extremely
toxic, the cis isomer (
Figure 22.5
)
was active against several forms of cancer, although it too had severe side
FIGURE 22.5
Platinum complexes currently in clinical use.
effects. Its applicability is still limited to a narrow range of tumours, and some tumours have natural resistance to
the drug, or develop resistance after treatment. Drug resistance can occur in several ways: increased drug efflux,
drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis.
Because of its side effects, limited solubility in aqueous solutions, and intravenous mode of administration,
a search for more effective and less toxic analogues has been initiated. Only a few of the thousands of platinum
complexes which have been evaluated have achieved routine clinical use. In addition to cisplatin, they include
carboplatin, oxaliplatin, and nedaplatin, the latter only approved as an anticancer agent in Japan (
Figure 22.5
)
.
They all have at least one N
H group, which is responsible for important hydrogen-bond donor properties.
The mechanism of action of cisplatin is relatively well understood. The drug enters cells by passive diffusion,
but also by an active transport mechanism. Ctr1, the major copper influx transporter, described in Chapter 8, has
e
4. Alfred Werner received the Nobel prize in chemistry in 1913 for his research into the structure of coordination compounds.
5. Horace Walpole wrote to his friend Horace Mann in January 28, 1754: “I once read a silly fairy tale, called “The Three Princes of
Serendip” : as their highnesses traveled, they were always making discoveries by accident, and sagacity, of things they were not in quest of:
for instance, one of them discovered that a mule blind of the right eye had traveled the same road lately, because the grass was eaten only on
the left side, where it was worse than on the right
e
now do you understand “serendipity”? For Walter Gratzer (a regular contributor for many
years to Nature) serendipity is not that when you drop your buttered toast on the floor that it falls, as it invariably does, buttered side down, but
that when you pick it up you discover the contact lens that you lost a few days earlier.
