In recent years, cancer has become a very tough disease to remedy (Ghani et al., 2012) . Research has proven that various types of cancers are treated with the use of Cisplatin chemotherapy. Some of the cancers that Cisplatin treats include; ovarian cancer, breast cancer, testicular cancer, lung cancer, head and neck cancer, bladder cancer, cervical cancer, brain tumors, and oesophageal cancer. Moreover, the cisplatin is administered through an injection into the vein. The effects of the injection often include; hearing challenges, suppression of the bone marrow, vomiting, and kidney problems. Trouble walking, numbness, heart diseases, electrolyte, and allergic reactions are also associated with this type of medication. This medication is very strong and should never be made on a pregnant woman as it could affect the baby.
Cisplatin consists of numerous medications; hence it is a platinum-based antineoplastic medication family. The medication works through creating a bond with the patient's DNA, thereby replicating and curing cancer. Licensing of the drug occurred in 1978 despite being discovered in 1845. The Cisplatin is a compound and is also referred to as cis-diamminedichloroplatinum (II). At room temperature, Cisplatin is either white or deep yellow- crystalline powder. It is soluble in N, N-dimethylformamide, and dimethylprimanide; it is slightly soluble in water.
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Over time, the medication can transform into trans-isomer. However, it maintains its stability under normal pressures and temperatures. The medication is clinically proven as a cancer cure; it goes a long way to present some effects to cancers affecting the bones, blood vessels, muscles, and soft tissue cancers. Despite researchers coming up with a more suitable medication for such cancers, curing them still presents challenges, although they are not life-threatening as they used to be. Application of cisplatin therapy with other cancer drugs has proven effective and necessary due to the considerable effects and drug resistance (DAGANI, 1985) .
Synthesis of the drug
In 1893, Alfred Werner elucidated cisplatin’s chemical structure despite M. Peyrone synthesizing the drug in 1844. However, it was until Rosenberg’s observation at Michigan State University that the drug gained scientific investigations. Moreover, Rosenberg pointed out that inhibition of cell division in Escherichia coli could be created through electrolysis products of platinum mesh electrodes, thereby being used in chemotherapy of cancer. It is in the potassium tetrachloroplatinate that the synthesis of this drug begins. The formation of tetraiodide occurs by reacting it with excess potassium iodide (ZAK & CERNIK, 2010) . The reaction of cisplatin with Ammonia leads to the formation of an isolated yellow compound K 2 [PtI 2 (NH 3 ) 2 ]. Precipitation of an insoluble silver iodide occurs when silver nitrate is added in the water while the presence is still seen in the solution K 2 [Pt (OH 2 ) 2 (NH 3 ) 2 ]. The formation of a precipitant, which is the final product, occurs when potassium chloride is added. Trans effect governs the addition of the second ammonia ligand in the triiodo. The first thing that occurs is the conversion of transplatin K 2 [PtCl 4 ] to Cl 2 [Pt (NH 3 ) 4 ] for the synthesis, and it is done by reaction with ammonia. Moreover, by reaction with hydrochloric acid results in the formation of trans product.
There are numerous side effects that limit the use of Cisplatin
The damage of kidneys is a great concern (Nephrotoxicity). It is essential that the kidney is checked; hence the dosage reduced in the event of kidney failure. Moreover, the prevention of kidney failure can be done through hydration. It is key to conduct nerve conduction before and after the treatment; this way, the anticipation of Neurotoxicity can be done. After the treatment, the possible side effects include; hearing disorder and visual perception. According to studies, there is an indication of archetypal presence in cisplatin. Since nausea and vomiting are some of the side effects associated with cisplatin use; however, it is managed by using a combination of corticosteroids and prophylactic antiemetics. Research has shown that in high emetogenic chemotherapy, ondansetron and dexamethasone is not as effective as the combination of ondansetron and dexamethasone together with aprepitant.
Ototoxicity (hearing loss) is also a side effect caused by cisplatin and has no treatment for this side effect. It is essential to use audiometric analysis to assess hearing loss. The electrolyte disturbance is risky as it may lead to hypocalcemia, hypokalaemia, and hypomagnesemia. It has been established that cisplatin is not the primary cause of hypocalcaemia as it affects people with low serum magnesium. After cisplatin’s several courses, Hemolytic anemia may be developed. Hemolysis can be caused by the reaction of the cisplatin-red-cell membrane with an antibody (Daoud, 1992). Cancer patients are injected with cisplatin as a sterile saline solution. The high concentration of chloride ions (~100 mM) in cisplatin enables it to remain in the bloodstream once injected. Through active uptake by the cell or passive diffusion, cisplatin, a neutral compound, enters the cell. The neutral cisplatin molecule undergoes hydrolysis. Moreover, a molecule of water replaces chlorine ligand, thereby positively charged species are generated, as described in the diagram below. A lower concentration of ion (~3-20 mM) results in hydrolysis in the cells hence later resulting in high water concentration.
The interior of the cell: Pt II (NH 3 ) 2 Cl 2 + H 2 O -> [ Pt II (NH 3 ) 2 Cl (H 2 O)] + + Cl -
[Pt I I (NH 3 ) 2 Cl (H 2 O)] + + H 2 O --> [Pt II (NH 3 ) 2 (H 2 O) 2 ] 2+
There are various targets for the cisplatin once inside the cell, including; the DNA; RNA; enzymes containing sulfur (glutathione and metallothionein); and the mitochondria. The effects that cisplatin has on DNA are not clear. However, a cell may die if mitochondrial DNA is damaged. The interaction between sulfur-enzymes and cisplatin results in cells resisting cisplatin. Cisplatin coordinates to DNA mainly through certain nitrogen atoms of the DNA base pairs; these nitrogen atoms (specifically, the N7 atoms of purines) are free to coordinate to cisplatin because they do not form hydrogen bonds with any other DNA bases.
There may be numerous formations of coordination between cisplatin–DNA complexes. The most important of the complexes formed are those that purine nitrogen atoms adjacent on bases replace on the same DNA strand. The 1,2-intrastrand adducts is the name of these complexes. Guanines are the most common purine bases involved in these adducts; however, there are also adducts with a single adenine and single guanine. The DNA helix often becomes kinked and purines to become detached upon the formation of adducts. The 1,2-intrastrand adducts with DNA cannot be formed by trans-DDP because of geometry. For the anticancer activity of cisplatin, the 1,2-intrastrand adducts that are formed between DNA and cisplatin are essential, considering that in killing cancer cells, the trans-DDP is inactive. Both in vivo (inside the host organism) and vitro (using cell extracts outside the host organism), studies were made in regard to the effects of both trans-DDP and cisplatin on DNA replication.
There was a revelation that the action of DNA polymerase was blocked by adducts of both trans-DDP and cisplatin in the studies of Vitro studies on both eukaryotic (mammalian) and prokaryotic (bacterial) cells. Polymerases were stopped from doing their job by 1,2-intrastrand adducts of cisplatin with DNA. On the other hand, Vivo studies showed replication was inhibited well by trans-DDP and cisplatin. In cisplatin destroying cancer cells, DNA replication is not the only factor considering that research has shown that trans-DDP is not an effective antitumor agent while the cisplatin is an effective one. The overall neutral charge of the cisplatin when it gets into the body is a sign that it is capable of crossing the cell membrane. A water molecule replacing one of the chlorides activates the cisplatin once in the cell. The fact that chloride concentration in a cell is less than in the bloodstream explains why chloride falls off. The basic nitrogen atoms on DNA easily replaces the water.
A guanine nitrogen atom from the DNA strand that is adjacent replaces the second chloride ion once bound to DNA (Agnihotri & Mishra, 2011) . The two DNA strands cross-linked by a platinum fragment within the double helix is the result attained. The tumor stops growing because the cell dividing the mitosis is prevented by the cross-linking. The DNA repair enzymes can repair the DNA damaged in healthy cells. However, in tumor cells, the DNA cannot be fixed since the 'kink' induced by the platinum cross-link is not recognized. Therefore, the tumor shrinks since programmed cell suicide – apoptosis occurs on the cell. In instances where the chlorides are adjacent, it essential to use the 'isomer' or cis form of the square planar complex. The cis geometry is suitable to fit in between the two double helix strands when the DNA guanine replaces chloride ligands. The cisplatin is a sign of hope; it has changed the culture of hopelessness and how people regard cancer, which is not the same; it was viewed decades ago. The impact of this drug on society is great as it has shown the capability of defeating cancer. It will change the fear of cancer and make a normal thing in society; it will generally be an additive to good health.
References
Agnihotri, N., & Mishra, P. (2011). Reactivities of radicals of adenine and guanine towards reactive oxygen species and reactive nitrogen oxide species: OH and NO2. Chemical Physics Letters , 503 (4-6), 305-309. https://doi.org/10.1016/j.cplett.2011.01.042
DAGANI, R. (1985). Anticancer Drug Cisplatin's Mode of Action Becoming Clearer. Chemical & Engineering News , 63 (50), 20-21. https://doi.org/10.1021/cen-v063n050.p020
Daoud, S. (1992). Cell membranes as targets for anti-cancer drug action. Anti-Cancer Drugs , 3 (5), 443-454. https://doi.org/10.1097/00001813-199210000-00001
Ghani, K., Trinh, Q., & Menon, M. (2012). THE PHANTOM MENACE OF PROSTATE CANCER SCREENING. BJU International , 109 (3), 324-326. https://doi.org/10.1111/j.1464-410x.2011.10881.x
ZAK, Z., & CERNIK, M. (2010). ChemInform Abstract: Diphosphorus Tetraiodide at 120 K. Cheminform , 27 (22), no-no. https://doi.org/10.1002/chin.199622009
