Chemotherapy and Chemotherapeutic Agents Cisplatin Synthesis and Mechanism of Action
Cancer
Three
of the top 10 major causes of mortality for adults over 60 are related to
cancer, which also accounts for about 12.5% of all fatalities globally each
year. Cancer is a disorder in which one or more cells lose the ability to
regulate their own growth, which can result in either a solid tumour or a liquid
form of the disease. Surgery, chemotherapy, and/or radiation therapy are the
primary forms of treatment for this disease, which is one of the most common
causes of death across the world. During
chemotherapy, low-molecular-weight drugs are administered to specifically
target and destroy cancer cells, or at the absolute least, to stop them from
growing. Numerous chemotherapy medications have been shown to have adverse
effects that include the suppression of bone marrow, lesions of the
gastrointestinal tract, hair loss, nausea, and the development of clinical
resistance. Because cytotoxic drugs have an effect on both healthy cells and
cancer cells, this phenomenon gives birth to these unintended side effects.
Cancer is a big financial burden in the Western world due to the ageing baby-boomer population. Additionally, it is only possible to calculate the cost to the community in terms of the wealth of various information, experience, and abilities that will be lost due to premature death. The need for innovative therapeutic medications and treatments is driven by the prevalence of cancer and the accompanying human and financial costs. Therefore, the introduction of anticancer and antimetastatic medicines has significant positive social and economic effects for everyone.
Chemotherapy
Chemotherapeutic agents, often known as antineoplastic drugs, are used to prevent or at least slow down the unchecked development and division of cancer cells. In 1940s the development of such agents started. The surgical removal of the tumour was the sole therapy option that had been made accessible up to this moment. Nitrogen mustards, a very powerful category of alkylating chemicals, served as the foundation for the very first pharmaceuticals ever developed.
There are
following chemotherapeutic agent classes
·
Nitrosoureas
·
Antimetabolites
·
Natural Products and Plants
Alkaloids
·
Anti Tumour Antibiotic
·
Hormonal Agent
Even while a vast variety of cellular nucleophiles
are capable of reacting with these highly electrophilic compounds, it is the
ability of these chemicals to attach alkyl groups onto DNA bases that results
in the critical lesion that kills cancer cells. One of the most horrifying
aspects of World War I—the use of sulphur mustard gas in chemical
warfare—ultimately led to the development of an innovative approach to the
treatment of cancer. During this same time period, a second group of cancer
chemotherapeutic medicines known as antimetabolites came into being.
Antimetabolites, in contrast to nitrogen mustards, interfere with the synthesis
of DNA precursors and/or imitate their functions. This either stops replication
from beginning altogether or causes mistakes throughout the process of DNA
replication, which eventually leads to the death of cancer cells. The efficacy
of the first drugs led to the development of a large number of new
antimetabolites in subsequent years. Since the invention of these initial
pharmaceuticals, a great number of additional chemotherapeutics have been
developed. These new drugs target not only the process of DNA replication but
also a wide variety of other biological targets found inside cells, such as the
microtubules that are necessary for the division of cells.
Cisplatin
Since
the discovery of cisplatin, or cis-diaminedichloro platinum(II),
[cis-(NH3)2PtCl2] (Fig. 1, (1A)), one of the most powerful anticancer drugs,
thousands of platinum complexes have been synthesised and investigated for
their anticancer properties. So far, clinical studies have been conducted on
five of these complexes: cisplatin (1 A) and carboplatin (1 B) over the world,
oxaliplatin (1 C) in a few countries, nedaplatin in Japan, and lobaplatin in
China (Salim et al., 2006).
Cisplatin is a platinum based chemotherapy agent used to treat various sarcomas, carcinomas, lymphomas, and germ cell tumors. Experiments in the early sixties in which the growth of Escherichia coli was studied as a function of the electric field - generated between platinum electrodes with aqueous NH4CI as the electrolyte - showed an unexpected filamentous growth, which was initially not understood. Subsequent experiments by the same investigators showed that the origin of the filamentous growth had nothing to do with the electric field. But was in fact caused by the presence of small amounts of platinum co-ordination compounds formed upon dissolution of the Pt electrodes in the NH4Cl containing solutions.
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Synthesis of Cisplatin
• Potassium
tetrachloroplatinate is reacted with excess of potassium iodide
• The tetraiodide so
formed is reacted with ammonia to form K2[PtI2(NH3)2], a yellow compound
• The insoluble
silver iodide is precipitated as the yellow compound is treated with silver
nitrate in water
• Addition of the
potassium chloride gives the final product.
• The main mechanism of the cytotoxic action involves the binding of cisplatin to genomic DNA in the cell nucleus to form interstrand and intrastrand cross-links.
• This interferes with normal transcription and/or DNA replication mechanisms and triggers cytotoxic processes that lead to cell death.
• Although DNA has many components with lone pairs of electrons where metal ions may bind.
• Early studies have made clear that cisplatin preferentially binds at the nitrogen atoms of the nucleobases (Guaninie).
• All bases do have
such nitrogens and have been found to be able to co-ordinate transition-metal
ions.
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