History:
The first platinum based anticancer drug was accidentally
discovered in the late 1960's by Dr. Barnett Rosenberg at Michigan State
University. Dr. Rosenberg was sending current through platinum electrodes
in ammonium chloride buffered solutions containing E. coli.
The intent was to get the negatively charged bacterial membranes to align
themselves along the induced magnetic field. The experiment resulted
in killing the bacteria, and after analyzing the solution it was determined
that the compound cisplatin (cis-diaminodichloroplatinate II) was the culprit.
This experiment with E. coli suggested that cisplatin had potential
anticancer properties. After nearly ten years of clinical trials
the drug finally received FDA approval for the treatment of testicular,
ovarian, head and neck, and small lung carcinoma. Since then cisplatin
has been a staple chemotherapy agent, grossing over $500 million annually,
of which Dr. Rosenberg receives four percent.
Structure/Function:
Cisplatin has a square planar platinum center that
coordinates four ligands, two chloride and two ammonium. The cis
formation of this compound is responsible for the anticancer activity exhibited
in tumor cells. Due to the cis square planar configuration the compound
is able to coordinate two adjacent guanine bases in DNA in a 1,2 intrastrand,
1,3 intrastrand, and interstrand manner. For the compound to
become active the two chloride ligands are replaced by either hydroxide
groups or water. The ammonium ligands are considered "stabile amines,"
where the bond dissociation energy is too great (approximately 70 kJ/mol)
to be broken in vivo. Therefore, any cisplatin derivative
with only changes to the leaving group (chloride ligands) will ultimately
have the same aquated counterpart. The only way to get different
active compounds is to change the stabile amine group. Later cisplatin
derivatives will be discussed to show the significance of changing the
leaving group and stabile amine.
Anticancer activity is due to aquated cisplatin
binding to DNA in the major groove and preventing replication. The
formation of a 1,2 or 1,3 intrastrand lesion induces great strain on the
DNA molecule, and causes the helix to "bend" up to 30° towards the
major groove. Interstrand lesions occur less frequently (5 - 10%)
and have slightly different mechanisms for preventing replication.
The Pt-N bond is too strong to be readily broken in the body, therefore
if the repair mechanism is unable to remove both guanine bases the DNA
will not be able to properly separate and replicate.
Here is the interstrand adduct formed by cisplatin. Although not occurring as frequently, these lesions have characteristics that prevent DNA replication. Click and drag the image to better view the molecules conformation.
Carbon Platinum
Phosphorus Oxygen
Nitrogen
Side Effects:
Cisplatin has been described as one of the worst
drugs to be given to man. One of the main reasons for cisplatin's
notoriety is the extreme nausea and vomiting that go hand in hand with
chemotherapy treatment. These effects used to be so severe that patients
would discontinue treatment, however today drug cocktails are given in
conjunction with cisplatin to alleviate these side effects. Another
main side effect of cisplatin is renal toxicity, this is where cells of
the kidney are damaged resulting in poor filtration of the blood.
This can be remedied by keeping the patient hydrated, as well as monitoring
BUN (Blood Urea Nitrate) levels to observe kidney performance.
Cisplatin Derivatives:
Initial cisplatin derivatives focused on changing
the leaving group in hopes to alleviate toxic side effects as well as increase
solubility in the blood. Carboplatin (cis-diamino-1,1-dicarboxylatocyclobutane
platinate (II)) was one of the first derivatives, and seemed to help with
the inherent toxicity of cisplatin, but proved to be ineffective in cells
resistant to cisplatin. This led to extensive work on finding a new
stabile amine that showed activity in cisplatin resistant cell lines.
One of the more recent strategies is to replace the ammonium ligands with
a 1,2-diaminocyclohexane (DACH) ring. These DACH platinum (II) compounds
have shown to be less toxic as well as very effective in cisplatin resistant
cells. In tumors that are nearly 100 fold resistant to cisplatin,
the DACH platinum compounds only see a 1-2 fold resistance. The only
drawback from the DACH platinum (II) compounds is a lack of water solubility.
This leads to extensive work in finding leaving groups that are non toxic
and increase the water solubility of the overall compound. Many dicarboxylato
compounds have been used to achieve these goals.
Platinum (IV) compounds have also been shown to
be effective in fighting cancer, where the active compound contains a platinum
center that coordinated four water or hydroxide groups. Research
of platinum compounds has also led to the discovery of other metal centered
compounds (i.e. gold) that possess anti-tumor activity. Therefore
the accidental discovery of cisplatin by Barnett Rosenberg has not only
produced a powerful anticancer drug, but also aided in developing a large
field of study for potential anticancer drugs.
Further information can be found on cisplatin as
well as other platinum anticancer agents at
Carbon Platinum
Nitrogen Oxygen
Carboplatin, a second generation platinum compound with the
ammonium stabile amine. This compound's carboxylic acid leaving
group reduces toxicity and increases the compound's water solubility.
The ammonium stabile amine conformation prevents this compound
from being effective in cisplatin resistant tumors
Carbon Platinum
Nitrogen Leaving
Group
The DACH platinum compounds have a new stabile amine that reduces the
chances of cross resistance with cisplatin. The two groups off
the platinum
center are the leaving groups, which are frequently composed of carboxylic
acid containing species to increase the water solubility of the DACH
platinum compounds.
http://www.ch.ic.ac.uk/local/projects/s_liu/Html/Cisplatin.html