Cisplatin and Other Advances in the Platinum Based Anticancer Field










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.


Platinum     Chloride   Nitrogen
Cisplatin, the first platinum anticancer drug.  View the planar
nature of the coordination center by clicking and dragging the molecule.



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.
 
 


Carbon     Platinum   Oxygen     Phosphorus   Nitrogen

The cisplatin induced 1,2 adduct is on the left, and the 1,3 adduct is on the right..  Click and drag to rotate the molecules and observe how the cis square planar conformation allows these lesions to form.
Click on the button to the left and the 1,2 intrastrand adduct will rotate for visual optimization
Pressing the button to the left will rotate the 1,3 adduct
 
 

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

Tumor Resistance:
    One of the major side effects to cisplatin chemotherapy is resistance shown  by tumor cells.  If an individual relapses after going into remission, the prevailing tumor cells can be up to 100 fold resistant to cisplatin.  Furthermore, these resistant cells can show cross resistance to many other cisplatin derivatives that utilize the same stabile amine.  The basis for resistance has not been completely elucidated, however it is believed that resistant cells are either able to tolerate more platinum lesions, or have the ability to remove a higher degree of lesions than their non-resistant counterpart.  The later of the two is believed to be the most probable mechanism for resistance.

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.


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.



 
 

    Further information can be found on cisplatin as well as other platinum anticancer agents at
 http://www.ch.ic.ac.uk/local/projects/s_liu/Html/Cisplatin.html