Cisplatin: The Anticancer Drug

CISPLATIN?

You may have heard of this name before or maybe a relative of yours may have been administered some as treatment. In fact, cisplatin is a well-known drug, particularly in the medical sphere. In this blog article, we will take a leap back to the 1970s to talk about one of the greatest accidental discoveries in modern science.  

The year 2020 marked 42 years since the U.S FDA (Food and Drug Administration) approved the first platinum-based cancer drug, cisplatin (since platinum in certain chemical make-up is potentially toxic to humans)

Let us reflect on how cisplatin was first synthesised. 

In 1844, an Italian chemist, Michele Peyrone, was the first to synthesise cisplatin, which was then known as Peyrone’s chloride for a long time.

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It was only a century later that the anticancer property of cisplatin was found. In 1965, Barnett Rosenberg (pictured above), a biophysical chemist at Michigan State University, was conducting an experiment where he was examining the effects of electromagnetic field on bacterial cell growth. Later, he noticed a very uncommon phenomenon: after exposure to electromagnets the cells had grown, but not divided. They kept growing to up to 300 times their normal size. Eventually, after two years Rosenberg found out that it was NOT the electromagnet that stopped the cell division but a product derived from the chemical reaction of ammonium chloride and the platinum used as the electrodes.

 This product was CISPLATIN, the basis of today's most widely used anticancer drugs. 

Chemical structure of cisplatin

The structure was first elucidated by Alfred Werner (Nobel Prize winner in chemistry) in 1893. Cisplatin or cis-diamminedichloroplatinum (II) is a coordination compound that adopts a square planar geometry.

The conclusion of Alfred Werner was as follows: platinum complexes in which platinum is in the +4 oxidation state are octahedral (d²sp³ hybridisation). Conversely, when platinum is in the +2 oxidation state, it forms square planar complexes (dsp³ hybridisation which can be shown using the Valence Bond Theory). In cisplatin, platinum is in the +2 oxidation state, hence cisplatin adopts square planar geometry (meaning all four ligands are in the same plane as the central metal ion).

Now that we know what cisplatin is, let us see how it operates in the body.

So far we know that cisplatin is a platinum-based chemotherapy medicine used to treat cancer, the second leading cause of death globally. 

Cancers develop when an uncontrollable and irregular mutation and proliferation of certain cells occur within the body. Such changes may be due to exposure to cancer-causing substances (such as benzene, arsenic compounds…), commonly known as carcinogens. The abnormal cells spread rapidly, destroying nearby tissues. The figure on the right shows an artistic representation of the replication of a cancer cell.

Cisplatin, which is injected intravenously (direct injection into the bloodstream through veins), works by inhibiting the multiplication of these cancerous cells. Cisplatin is transported around the body in its neutral, relatively unreactive form. For cisplatin to be reactive, it has to be activated to cis-diamminediaquaplatinum(II). After entering a cell, cisplatin’s activation is achieved by the substitution of both chloride ligands by water since chloride is a good leaving group being a weak base (outlined below).

The complex being positively charged has a more favourable interaction with the negatively charged DNA backbone. This leads to a covalent binding with specific sites on the DNA through an exchange of water ligands, forming a sharp twist or curve of the DNA. This irreversible binding of the DNA blocks the mechanism of the DNA repair and thus inducing cell death by a process called apoptosis.

Apoptosis: It is a kind of programmed “cellular suicide” that occurs in multicellular organisms.

Unfortunately, cisplatin can also affect normal, healthy cells particularly those which multiply quickly (blood cells and hair cells), leading to their death. Cisplatin may reduce the production of blood cells, leave patients vulnerable to infection. Therefore regular blood tests are required to control the blood cell levels.

Also, it is worth noting that cisplatin has some major side-effects that may limit its effectiveness. The preponderant one is its toxicity, which particularly damages the kidneys, gastrointestinal tract and nervous system.

Rosenberg and his team at the Institute of Cancer Research (ICR) tested multiple analogues of cisplatin whereby the ligands (the molecules attached to the central metal ion via coordinate/dative covalent bonding) were altered and tested.

Analogues of Cisplatin

In spite of the widespread success of cisplatin, several thousand analogues have been synthesised and tested to enhance their therapeutic properties. Analogues are basically non-identical compounds possessing chemical similarities. Around a dozen of these analogues have been evaluated by Rosenberg and his colleagues in clinical trials.

Space-Filling Model

The most successful analogue synthesised is known as carboplatin which has provided a distinct edge over cisplatin and achieved worldwide approval for the treatment of a wide range of cancer in 1989. Compared to cisplatin, carboplatin offered a dramatic reduction in toxicity, but at a reduced activity.

Oxaliplatin is an analogue of cisplatin approved in the United States in 2002 for clinical use against advanced colorectal cancer and is the only platinum compound to have displayed activity against colorectal cancer.

The list of side effects does not stop here - two other important ones are resistance and nephrotoxicity which clearly reduce the efficiency of cisplatin. 

•          Cisplatin Resistance:

Resistance is a natural cellular self-defence process manifested by evolution to defend cells against harmful natural products.

Patients usually have a good initial response to cisplatin-based chemotherapy but later recurrence of cancer occurs, because the development of cisplatin resistance significantly reduces its clinical effectiveness. To support this, in 2015, it was estimated recurrence occurs in 25% of patients with early-stage disease and more than 80% of patients with advanced disease.

Recurrence: This occurs when cancer comes back weeks, months or even years after the cancer was treated.

•          Nephrotoxicity

Nephrotoxicity is the deterioration of the kidney's function due to toxic chemicals and medications. Some factors that increase cisplatin nephrotoxicity are: older age, smoking, inconvenient dose and the female gender.

Researchers in action

As already explained, cisplatin has a plethora of limitations and many patients still wonder why the use of cisplatin in chemotherapy has not been discontinued so far. Well, up to now no drugs have been found/synthesised to be more effective against cancer than cisplatin. Henceforth, researchers are designing and analysing methods in order to reduce the limitations associated with cisplatin.

In 2012, researchers at the University of Kansas Cancer Center have designed a new formulation of cisplatin named HylaPlat. A particular case was an eleven years old shepherd dog named Cody who suffered from cancer (Lymphoma) and within weeks of administration of HylaPlat, the dog was completely cured of cancer.                                                                                       

FROM DOGS TO HUMANS!!

The researchers are optimistic: Based on the results, the balance of safety and effectiveness seems to be good. There is hope for starting human trials. 

To read more about how Cody recovered from his cancer click here

Isn’t it fascinating how back in the 1970s if Rosenberg and his team did not raise the intriguing question,

“If platinum could kill fast-growing bacteria, can it also kill similarly fast-growing cancer cells?”,

the rate of testicular cancer would possibly not have been reduced by more than 90% today. Back then before the discovery of cisplatin, for anyone diagnosed with cancer, it was whispered in their ears – only almost one of four people survived.

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It was those curious minds that led to the incredible story of turning discovery into health.

“The important thing is not to stop questioning. Curiosity has its own reason for existence.”- Albert Einstein

Special Thanks goes to Adel Jeanne for his huge part in this work and continuous support.

Stay tuned for the next article!