Greetings to everyone! Today, I shall discuss with you guys about the significance of one of the important drugs in medicinal chemistry. Without the discovery and development of this drug humankind would have faced tremendous challenges and we might have lost many dear ones. Well, this drug has been used in numerous human cancers from around 1970 and till date the interests on studying and new research on it has been growing and progressing. Yes, it is cisplatin or cis-diamminedichloroplatinum (II) which is a well known chemotherapeutic drug. We shall be discussing about it’s properties, roles in human body and it’s mechanism of action in our body.
Discovery and Initial Impression on Cisplatin
Although the drug was first synthesised by M. Peyrone in 1844 but it did not gain sufficient scientific investigations until the 1960’s when Rosenberg at the Michigan State University studied the drug and proposed that certain electrolysis products of the platinum electrodes were able to inhibit cell division in bacterium E. coli (Escherichia coli). This conclusive evidence created a more pronounced interests in the possible use of these products in cancer treatment.
Cisplatin is a metal complex having 3rd row transition series metal platinum with a square planar geometry. Physically it is a white or deep yellow to yellow-orange crystalline powder at room temperature. It is sparingly soluble in water but soluble in N,N-dimethylformamide. It is stable under standard pressures and temperature but it may transform to the trans form slowly over time.
Uses and Activity of Cisplatin
Cisplatin has been used for various germ cell cancers including bladder, head and neck, ovarian and testicular and lung. It is also effective against other types of cancers such as carcinomas, lymphomas and sarcomas. Among many other chemotherapeutic drugs, cisplatin is one of the most compelling ones as can be witnessed by the fact that it was the first FDA-approved platinum compound for cancer treatment. This comprehensively led to the interests in platinum (II) and other platinum group metal (PGM) containing compounds as a potential anticancer drugs.
The mode of action of the drug has been linked to it’s ability to intrastrand linking with the purine bases on the DNA thereby interfering and preventing DNA replication and causing DNA damage of the cancerous cells i.e., inducing apoptosis in cancer cells. However because of some undesirable side effects such as severe kidney problems, hemorrhage, allergic problems and hearing issues specially in younger patients, other platinum containing anti cancer drugs namely carboplatin, oxaliplatin and others have also been used. The combination of cisplatin with other anti cancer drugs has been considered to overcome the drug-resistance and reduce toxicity. This has been applied as novel therapeutic strategies for many cancers in human beings. In this study, we will limit our reach to cisplatin only. We might study other platinum containing drugs in later articles to come.
Mechanism of Action of Cisplatin
Cisplatin is always used intravenously or injected intravenously. It gets activated once it reaches the target cell. Cisplatin has 2 amino groups (-NH2) and 2 Cl atoms linked to the Pt center. In the cell cytoplasm, the two chloride atoms are displaced by two water molecules. The resultant hydrolysed product is a potent electrophile that can react with any nucleophile including the N donor atoms on nucleic acids (DNA and RNA). Thereby forming an aqua complex in the blood stream and then it goes to bind with the DNA molecule.
Cisplatin binds with the N-7 reactive site of the purine base (such as in guanine) and causes the damage to the cancerous DNA cells. This stops the replication process of the infected DNA and blocks the cell division process ultimately leading to the apoptotic cell death. Platinum binds with the two nitrogen atom of guanine base of nucleic acid in one strand. This kind of binding is called intrastrand linkage. The 1,2- intrastrand cross-links of purine bases with cisplatin are considered to be most effective among the changes caused in the DNA.
Can Transplatin Show Anticancer Activity?
The use of suitable isomer is indeed important and sometimes cautious too. I think I don’t have to let you know about the thalidomide disaster. (Shortly, one of the isomer of thalidomide was very dangerous to pregnant lady as well as human beings, whereas other had beneficial medicinal properties. So for drug delivery, these two have to be separated before marketed).
The simple answer to the question is NO! Yes, we can’t state the same for transplatin to show anticancer properties. It is because the trans isomer can not form the intrastrand linkage needed to stop the DNA replication.
Side Effects of Cisplatin
Yes! Cisplatin does have some side effects too irrespective of the good effects it has on the cancerous cells. The covalent adduct formed by the interaction of cisplatin with DNA is the root cause for cytotoxic effect of cisplatin. The two major side effects includes nephrotoxicity and neurotoxicity. Other toxicity includes hepatotoxicity and cadiotoxicity.
Nephrotoxicity: The kidney accumulates cisplatin to a greater extent than any other organ. Carnitine is a quaternary ammonium compound which is essential for the transport of fatty acids from the cytosol to the mitochondria during the breakdown of lipid to generate metabolic energy. Kidney is damaged by the inhibition of synthesis of Carnitine and also by its reabsorption by the proximal tubules of nephron leading to the decreased production of Carnitine.
Cardiotoxicity: Leakage if lactate dehydrogenase(LDH) and creatine kinase(CK) from cardiac myocytes results in the cardiotoxicity. It is followed by cisplatin induced lipid peroxidation of cardiac membranes. The cisplatin induced toxicology results in degeneration and necrosis of cardiac muscle fibres and vacuolated cytoplasm of many muscle cells.
Cisplatin also induces other organ toxicities such as ototoxicity, gastrotoxicity, reproductive toxicity and allergic reactions. Due to these side effects of cisplatin one substituent of cisplatin is used which is known as carboplatin. Carbolplatin does not show neurotoxicity and nephrotoxicity.
Conclusion
Cisplatin is undoubtedly one of the most effective anticancer agent used in the treatment of solid tumors. It has been used for the cure of different types of neoplasms including lung, ovarian, breast, brain, kidney and testicular cancers. The cytotoxic drug induces apoptotic cell death thereby inhibiting the cell division of the tumor cells. However, cisplatin chemotherapy also poses some side effects as discussed earlier. Combination of cisplatin with other compounds constitutes one of the best approach to overcome drug resistance and reduce toxicity. Combinatorial strategies such as reduced cisplatin uptake and reduced inflammation may target multiple mechanisms, thus offering best chances for clinically meaningful prevention.
This is all for today’s blog. Let me wrap up post now with a promise to meet again with another chemophilic post.
Cisplatin in cancer therapy: molecular mechanisms of action
The "Accidental" Cure—Platinum-based Treatment for Cancer: The Discovery of Cisplatin
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PS The thumbnail image is being created by me using canva.com taking template image from Ikris pharma
