Cisplatin: Synthesis, Work, Effects, and Safety

Cisplatin is the first metal-based, highly-toxic anticancer drug. SP-4-2 diamminedichloridoplatinum (II) is commonly known as cisplatin. It has chemotherapeutic properties and is among the drugs used to treat head, neck, testicular, ovarian, lung, cervical, bladder, and other cancers. For its anticancer activity, cisplatin works on various mechanisms.

Chemical Structure of Cisplatin

• The allowable and most widely used mechanism involves DNA lesions generation after interacting with purine bases.
• As a result, different signal transduction pathways get activated, which leads to apoptosis.
• However, the two challenges limiting its application throughout the world are drug resistance and side effects.
• To minimize these challenges, numerous therapies are used, which are proven effective in cancers.

Read More: Cis Trans Isomerism

Key Terms: Cisplatin, Synthesis, DNA, Anti-cancer, Chemotherapy, Toxicity

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How is Cisplatin Synthesized? 

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In 1980, Inventor Richard N. Rhodha published the most efficient method to synthesize cisplatin in his patent, “A process of preparing cis-[PtCl₂(NH₃)₂]”. Before him, Dhara provided the steps to prepare cisplatin in 1970, but his work was not patented. Synthesizing cisplatin is a multi-step process. Commercially available tetrachloro and hexachloro salts of platinum (II) and (IV), such as K₂PtCl₄ and K₂PtCl₆, are used to prepare cisplatin. Various steps involved during synthesis are:

Step 1 – An aqueous solution of chloroplatinic acid is heated to 55°C. Dropwise addition of KCl is done till we see K₂PtCl₆, a yellow precipitate. It is done till no KCl is left in the solution. The solution is then cooled and filtered to get the residues. The residue is then washed with ethyl alcohol and then left as such for platinum recovery. The reaction is described below-

H₂PtCl₆ +2KCl → K₂PtCl₆ +2HCl

Step 2 – The dried precipitate is added in water, following dropwise addition of N₂H₄.2HCl. This is done till the yellow precipitate completely disappears. The solution is heated and cooled so that no precipitate is left. The following reaction takes place-

2K₂PtCl₆ +N₂H₄.2HCl → 2K₂PtCl₄ +N₂

Step 3 – The product of the above step, potassium tetrachloroplatinum (I), is mixed with KI till it forms a black precipitate of K₂PtI₄. It is heated at 85°C and cooled to obtain a maximum precipitate.

K₂PtCl₄ +4KI → K₂PtI₄ +4HCl

Step 4 – The product of the above reaction is mixed with dilute NH₄OH until the black precipitate disappears completely. The solution is heated to 60°C and then cooled for an hour. Neutral pH should be maintained while performing this step.

K₂PtI₄ +2NH₄OH → cis-Pt(NH₃)₂ I₂ +2KI+2H₂O

Step 5 – The product of the above reaction is dissolved in aqueous AgNO₃ to form an AgI precipitate.

cis-Pt(NH₃)₂ I₂ +2AgNO₃ +2H₂O → cis-[Pt(NH₃)₂ (H₂O)₂](NO₃)₂ +2AgI

Step 6 – KCl is added to the product of the above step as soon as possible after obtaining it. The filtrate is collected and washed thoroughly to remove impurities. The final product is crystallized into several steps to obtain cis-Pt(NH₃)₂ Cl₂ as the end product.

cis-[Pt(NH₃)₂ (H₂O)₂](NO₃)₂ +2KCl → cis-Pt(NH₃)₂Cl₂ +2KNO₃ +2H₂O

Synthesis of Cisplatin

Read More: What is an Ideal Solution?

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How Does Cisplatin Work? 

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In the bloodstream, the level of chloride is high. Hence, cisplatin remains unchanged. Some injected cisplatin binds with albumin, a plasma protein, and travels farther in the blood without any chemical reaction. As a result, a large amount of cisplatin is left unchanged. The leftover cisplatin reaches the tumor cells with the help of a plasma membrane. Now, cisplatin starts its work.

• Since the chloride concentration is lower in cisplatin, the latter replaces one of the chloride ligands with the water ligand.
• After this, cisplatin forms reactive oxygen species, like superoxide, hydroxyl radicals, resulting in oxidative stress.
• This phenomenon is responsible for the apoptosis of cells and DNA damage.
• The main target of cisplatin is genomic DNA (gDNA).
• Cisplatin enters the DNA nucleus and binds to the potential binding sites on the DNA strand.
• Cisplatin removes cancerous adducts from DNA, resulting in anticancer activity.
• With a continuous cisplatin dosage, DNA bends, twists, and changes its course from cancerous to anti-cancerous.

Workflow of Cisplatin

Read More: Covalent bonds

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Effects of Cisplatin 

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There can be severe health issues if cisplatin is not handled carefully. Some of those side effects are-

1. Extravasation – It is the phenomenon by which a drug or medicine leaks from the veins and passes to the surrounding tissues and blood. In case extravasation is suspected, it should be stopped or controlled at once. Antidotes, like sodium thiosulfate, should be given to the patients to prevent leakage.
2. Leukaemia –  It occurs years after the treatment with cisplatin is over.
3. Tumour Lysis Syndrome – The chances of getting tumor lysis syndrome increase if the chemotherapy goes with various chemicals. In such cases, chemicals to reduce uric acid are given to the patient.

Other side effects of cisplatin are:

• Dark urine
• Hiccups
• Dry mouth
• Vomiting
• Mild nausea
• Dry skin
• Dehydration
• Loss of taste
• Diarrhoea
• Decreased sweating

Read More: Coupling Reaction

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Toxicity Caused by Cisplatin 

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Various toxicities are witnessed in the patient's ongoing cisplatin treatment. Some of those are:

• Neurotoxicity: Neurotoxicity or peripheral neuropathy is a dose-related issue. It may occur after discontinuation of the course. If neuropathy is diagnosed, then the cisplatin dosage is altered or can lead to discontinuation of treatment.
• Gastrointestinal toxicity: Certain metabolic reactions may result in vomiting and nausea during cisplatin treatment.
• Nephrotoxicity: There are chances of the occurrence of acute renal failure during cisplatin treatment. Proper hydration before initiating the therapy can prevent renal toxicity.
• Ocular toxicity: It is also known as retinopathy. From cortical blindness to the loss of color discrimination, the side effects of cisplatin can be severe. Recovery is only possible after discontinuing the course.
• Ototoxicity: A check-up of the heart is a must during cisplatin treatment. Hearing loss, ringing ears, and reduced ability to catch conversations are some of the symptoms seen in patients. Deafness can also occur in severe conditions. However, it is not a common side effect.
• Myelosuppression: Infections may occur if the patient has morbidities. Patients are kept under intense surveillance in this case. Dose modification or complete termination of treatment is the solution to prevent myelosuppression.
• Gonad toxicity: Usage of cisplatin leads to premature menopause due to ovarian failure. Cisplatin is toxic to gonads. It can cause spermatogenesis.

Read More: Organic Solvent 

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Safety Measures While Handling Cisplatin 

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Various safety measures must be taken while handling cisplatin. Some of them are-

• Cisplatin, if used with other chemicals, can cause severe health issues. It should not be used with these medicines concurrently:
  • Clozapine
  • Chloramphenicol
  • Alpha-lipoic acid
  • Barictinib
  • Denosumab
  • Fosphenytoin
  • Nivolumab
  • Palifermin
  • BCG
  • Aminoglycosides
  • Natalizumab
  • Siponimod
  • Tacrolimus
  • Tertomotide
• Pregnant women must take special care during ongoing cisplatin treatment. Cisplatin can cross the placenta, reaching breastmilk, which is harmful to infants.
• Patients who have blood pressure issues should not undergo cisplatin treatment.
• Hypersensitive patients are strictly prohibited from undergoing cisplatin treatments. Their immune system may create problems resulting in non-curable allergies.
• The medical expert must take care of the blood count before initiating the treatment, during treatment, and after cisplatin treatment.
• Pediatric patients must be administered audiometric testing during cisplatin treatment. Their testing should continue for several years after discontinuation of the therapy.
• Patient ongoing cisplatin treatment should be monitored carefully. In case of any infusion, ocular changes, neuropathy, or any other signs of infection are observed, it must be controlled immediately.
• Open communication between medical staff plays a vital role in treating side effects or cons during cisplatin treatment. Therefore, the interprofessional team must communicate among themselves from time to time.

Read More: Gatterman Reaction

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Things to Remember

• Cisplatin is a highly toxic anticancer drug used to cure ovarian, lung, cervical, bladder, neck, head, and testicular cancers.
• It is synthesized using tetrachloro and hexachloro salts of platinum.
• Cisplatin targets genomic DNA changing its structure and resulting in anti-cancerous DNA formation.
• A high dosage of cisplatin causes extravasation, leukemia, and tumor lysis syndrome.
• Other effects, like dry mouth, hiccups, dry skin, dehydration, loss of taste, decreased sweating, etc., are also seen if cisplatin dosage increases.
• As ovarian failure is brought on by cisplatin usage, menopause occurs prematurely.
• Cisplatin causes various toxicities, like ocular, neuro, nephron, oto, gastrointestinal, gonad, and myelosuppression.
• Various safety measures must be taken while handling cisplatin before, after, and during medication.