Abstract
The primary aim of anticancer therapies is to induce the death of tumor cells. Cisplatin has done a good job in achieving this aim, which explains why it is the most commonly used adjuvant therapy of cancers. However, the success of applying CDDP and any other platinum compounds for cancer chemotherapy depends enormously on the ability to manage its side effects. This paper reviews the studies and literatures on cisplatin and some other similar platinum compounds. It presents its history and background, chemistry, mechanism of activity, as well as the side effects.
Introduction
The cisplatin has been described as a tiny little drug molecule that is made up of platinum ion located at the center of a flat square having two molecules of ammonia and chloride ions making up the corners. It is also known as CDDP or cis-[Pt(II)(NH(3))(2)Cl(2)] ([PtCl2(NH3)2]. Among the huge number of chemotheraphy drugs used in the treatment of cancer, Cisplatin has been described to be one of the most potent . It was the discovery of the cisplatin that led to the proliferation in the interest in metal-containing compounds, especially in platinum (II), as potential drugs for cancer cure . The CDDP has been able to treat and cure a good number of cancer types among which are cancer of the blood vessel, muscles, bones, soft tissues, and sacoma cancers. Thanks to the CDDP such cancers are no longer life threatening as their occurrences are being met with better prognosis . The clinical successes that have been achieved with the cisplatin and its other derivatives has encouraged scientists to keep making efforts in order to develop many other metal-based that would be effective in the treatment of cancer. However, as at this moment, only the oxaliplatin and carboplatin has been given approval for clinical practice worldwide. There are some that has been given a limited approval this includes the heptaplatin, lobaplatin, oxaliplatin, and nedaplatin.
This paper review is aimed at the describing the cisplatin as an anti-cancer drug, its mechanism of activity and resistance, its background, chemistry, side-effects, and why it still remains one of the most potent drugs for the chemography treatment of cancer.
The cisplatin was first synthetized in the year 1845 and its structure was deduced in 1893 by Alfrew Werner. Its synthesis is a fine illustration of the chemical principle termed the Trans effect . The cancer curing potential of CDDP was discovered in the year 1964, which opened a new era to the field of cancer treatment. How the cisplatin can be generated from the electrolysis of electrodes of platinum was discovered in the 1960s by Rosenberg and some of his colleagues. This discovery occurred after Barnett Rosenberg attempted to examine the role of electric currents in cellular division. During the course of the experiment, he discovered that the E.coli started taking a spaghetti-like shape, instead of their normal shape. He later found out that this alteration of shape is as a result of the inhibition caused by the presence of the cis form of the platinum(IV) complex,[PtCl4(NH3)2]. Afterwards, Rosenberg and his colleague succeeded in conducting a good number of platinum complexes tests on rat sacomas.
Though the cisplatin is best known as an anticancer drug, its discovery in 1845 was by an M Peyrone. As a result, it was initially referred to as “Peyrone’s salt” . The very first time a cisplatin based cancer treatment was applied to a cancer patient was in 1971. After observing its successes, it was made available as Platinol for clinical practices in the year 1978. Several research and studies conducted afterwards have shown clearly that the CDDP has a lot of clinical benefits but its efficiency also comes along with some tumor resistance and toxic side effects. These side effects, most likely, results into secondary malignancies.
The Chemistry of Cisplatin
The structure of cisplatin was not known until after Alfred Werner developed the theory of coordination chemistry in 1893. It was he who was able to show that ammonia can have a dative/covalent bonding with a metal ion like platinum +2 by donating its lone pair of electrons. The square-planar structure of the cisplatin was confirmed after Mills and Quibell was able to demonstrate its chirality, in 1935, using optical data rotation.
The Cisplatin Structure
The chemical formula for cisplatin is Pt(NH3)2Cl2. It has a molecular weight of 300.045. It is soluble in water and is delivered to the body in aqueous form.
Synthetic scheme for the synthesis of cisplatin
The procedure for the synthesis of cisplatin goes thus; a saturated solution of KI is added to K2[PtCl4] which converts it to K2[PtI4]. Ammonia is added which leads to the formation of cis-[PtI2(NH3)2] which is then collected and dried. Aqueous solution of AgNO3 is added which makes AgI to be precipitated and discarded. The addition of KCl results in the precipitation of the final product, i.e., cis-[PtCl2(NH3)2] in its powdered form.
Mechanism of Activity of Cisplatin
The cisplatin forms a platinum complex inside a cell. This platinum complex formed binds with the DNA and cross-links it. The manner in which the DNA is cross-linked makes the cells to undergo apoptosis, which is known as a systematic cell death. One of the methods in which this is achieved is that the cisplatin damages the DNA, once the DNA is damaged its repair mechanism gets activated and any cells found unsalvageable would be made to die.
Also, the mechanism of the CDDP is yet to be clearly understood . Due to this, there is a need for a better understanding of the molecular mechanism responsible for the modulation of the cellular responses in order to create and enhance new strategies for the therapeutic use of the cisplatin.
Results from several demonstrations have shown that when the chloride ligands of cisplatin are dissolved in an aqueous medium it undergoes a nucleophilic displacement by water . This discovery has led to speculations regarding the significance of aqueous forms of cisplatin in the production of anticancer activity. Several literatures have been written which reports the interaction of cisplatin with DNA constituents in aqueous systems under in vitro conditions with little or no chloride present. Horacek and Drobnik observed, from their spectrophotometric studies of the affinity of cisplatin for DNA, that an increase in the level of chloride lowers cisplatin’s affinity for DNA.
A perusal into many literatures on cisplatin has shown that the mechanism of action of CDDP is not well understood yet. In reality, if the mechanism of action of cisplatin is to be determined, specific analytical methodologies need to be developed. These methodologies should be capable of identifying and quantifying all the various platinum compounds that could be produced in the biological tissues.
Schematic drawing of CDDP uptake and efflux processes in the cell. Adapted from Katano et al.
Side Effects of Cisplatin
- Cisplatin is nephrotoxic. A couple of evidences have shown the part the CDDP plays in the inflammatory pathogenesis. Experiments conducted on rats also shows that the cisplatin is also responsible for the down-regulation of hepatic cytochrome P450 and the induction of acute renal failure. The CDDP is able to achieve this by interacting directly with the sulfhydryl groups.
- Cardio-toxicity. This has been discovered to be associated to the Cisplatin treatment. It has been observed that the combination of antineoplastic chemotherapy with CDDP is likely to bring about the occurrence of alterations of the electrocardiogram. This alteration includes the emesis of different grades and the prolongation of the QT-interval (the interval between the start of Q wave and the end of T wave).
- Heptatoxicity. Though this has not been given a due attention, however, the research conducted in rats has shown that CDDP increases the peroxidation of lipid and also changes the thiol status of the tissues with concomitant changes in the enzymatic antioxidants.
- Alteration of some pharmacokinetic behavior: Results from findings has shown it clearly that if cisplatin is administered by rapid intravenous injection, and not through infusion, there will be a significant alteration in some pharmacokinetic behavior.
Conclusion
Most of the reports cited in this paper have provided a good number of information as regards the chemistry of cisplatin. As a result of the lack of success of the extensive synthetic efforts which has been targeted at identifying and isolating additional platinum complexes with less toxicity and enhanced anticancer activity than CDDP, more rational approaches should be made for the identification of new agents.
It is noteworthy to mention that, Cisplatin has played an enormous role in the history of coordination chemistry. It serves as a perfect example for the illustration of both geometric and geometry isomerism. Also, how the cisplatin can be generated from the electrolysis of electrodes of platinum was discovered in the 1960s by Rosenberg and some of his colleagues after an attempt to examine the role of electric currents in cellular division.
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