Cisplatin

Generic name: Cisplatin

Commercial names:

Randa 

Platinoxan       

Platidiam         

Platamine        

Plastin 

Neoplatin         

Lederplatin       

Citoplationo     

Cisplatyl          

Cisplatine

Cismaplat        

Carboquone     

Briplatin           

Biocisplatinum 

Abiplatin

Structure:

Therapeutic Use:

Cisplatin is used for the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer.

Mechanism of action:

Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents add alkyl groups to many electronegative groups in cells, for example DNA. So, they inhibit DNA replication, tumor cells can´t divide and abnormal cell proliferation stops.

Alkylating agents act by three mechanisms that lead disruption of DNA function and cell death: alkyl groups attach to DNA bases, but repair enzymes try to replace the alkylated bases however they end up fragmenting the DNA, preventing DNA synthesis and transcription; cause DNA damage because of the formation of bonds between atoms in the DNA which prevents DNA from being separated for replication or protein synthesis; and induce mispairing of the nucleotides leading to mutations.

Side Effects:

v Increased risk of getting an infection from a drop in white blood cells;

v Tiredness and breathlessness due to a drop in red blood cells (anaemia);

v Bruising more easily due to a drop in;

v Tiredness (fatigue) during and after treatment;

v Feeling or being sick can be severe;

v Cisplatin can cause kidney damage;

v You may have some hearing loss, especially with high pitched sounds;

v This drug may have a harmful effect on a developing baby;

v Women may stop having periods (amenorrhoea) but this may only be temporary;

v Loss of fertility;

v Loss of appetite may occur a few days after your treatment;

v Numbness or tingling in fingers and toes can cause difficulty with fiddly things such as doing up buttons;

v Ringing in the ears (tinnitus) happens in about 3 in 10 people (30%), but nearly always gets better on its own;

v Loss of taste or a metallic taste may occur;

v Allergic reaction (rare).

*http://www.cancerresearchuk.org/cancer-help/about-cancer/treatment/cancer-drugs/cisplatin#common

Mutagens

The definition of the term mutagen is a chemical or physical agent that induces mutations. This definition is important because distinguishes mutagens from other environmental agents that cause cell damage in a way that it’s not a mutation. This mutagens definition also distinguishes between the real mutagenic agents and the agents that cause DNA damage without leading to mutations, for example agents that have as an effect DNA molecules fragmentation. This kind of damages can block replication and lead to cell death, but they’re not truly mutations, so the agents that cause this kind of effects are not mutagens.

A lot of chemicals that occur naturally in the environment possess mutagenic activities (ex. Micotoxins produced by fungi) and these mutagens have been complemented nowadays by chemical mutagens produced by human industrial activity. Beyond these chemical agents, physical agents, for example radiations, are mutagens as well. Most organisms are exposed to quantities, that can be superior or inferior, of these multiple mutagens, and so that the genomes of these organisms suffer damage. 

There can be some overlap between different categories (for example mutagens that are also carcinogens) but each one of the different types has specific biological effects. Mutagens can operate in 3 different ways:

• Some act as base analogs and what happens is that they are confused with nucleotidic bases being mistakenly used as substrates of DNA synthesis on the replication fork (Ex. 5-bromouracil).

• Some react directly with DNA, taking to structural changes that lead to miscopying of the template strand when DNA is replicated. These structural changes can be very diverse (ex. UV radiation; deamination agents; etc…).

•  Some mutagens act indirectly on DNA. This because they don’t affect directly the DNA structure, but instead induce cells to synthesize chemicals like peroxides that possess direct mutagenic activity. 

Oncogen

Oncogen is a substance or agent causing oncogenesis. 

This means that the substance/agent will induce the formation of tumors. This can happen if a proto-oncogene (a normal gene that will become an oncogene by mutation or increased genic expression) suffers mutation and the cell will undergo on disordered multiplication. 

In turn, this can convert in cancer with a virus infection or at  higher rates of mitosis, which will promote more mutations while mechanisms of apoptosis and DNA reparation will shut down.

Hypermutation

Hypermutation is a modification of a DNA sequence that occur very frequently in the genome, and these mutations are spontaneous errors that occur during replication, because they´re caused by incorrect repair of mismatches.

Hypermutation can also happens by deamination of cytosine bases to produce uracil, followed by excision of the uracil by glycosylase to form AP sites. On the next replication, a nucleotide is inserted at opposite AP site and after another replication, the mutation is stabilized.

This mutation occurs in some vertebrates, including humans, to generate a diverse range of immunoglobulin proteins to deal with all possible antigens.  These point mutations happen, for example, in the V (variable) gene region of an immunoglobulin gene that encode the antigen-binding sites, resulting in the amino acid modification in the heavy and light chain of the antibody V regions. So, these regions are responsible for the affinity maturation and specificity required to produce effective neutralizing antibodies.

Carcinogen

 Carcinogen is an example of mutagen, it is a chemical or physical agent that causes mutations.  A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. 

 Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. In conclusion, the carcinogen causes cancer, one neoplastic transformation of eukaryotic cells.

Leaky Mutation

A leaky mutation is a type of mutation that partially impairs a certain characteristic or function in the mutant, rather than eliminating it completely. For instance, normal auxotrophic mutants don´t grow at all in the lack of the appropriate medium. However, it is common to find some leaky mutants that grow very slowly in the absence of the appropriate supplements.

In this mutation, the amino acid substitution isn’t enough to completely deactivate a certain function of the protein. Instead, it slows the function or makes it less effective. If the function was completely erased by the amino acid substitution, it would be called a loss-of-function mutation.

Deletions and duplications can be used to distinguish between levels of loss of function so as showed by the picture below.

Figure 1.  Representation of loss of function caused by a leaky mutation (b) and respective phenotype of gene M/+ in this type of situations compared with a control group (a) and respective phenotype of the gene +/+..
Therefore, in leaky mutants is possible observe wild-type phenotype of  this gene due to the allele duplication relative to this gene compensating the loss of function caused by a deletion of an allele of  this gene.

Streptomycin

Streptomycin is an antibiotic commonly known for being the first medical solution against tuberculosis. This was the first aminoglycoside molecule, consisting of amino-modified sugars, to be discovered (October 19, 1943 by Albert Schatz). This bactericide acts as a protein synthesis’ inhibitor; it binds to the ribosome of bacteria interfering with the binding of formyl-methionyl-tRNA. This phenomenon will directly affect the reading of codons, which will lead to inhibition of protein formation and, as consequence, the death of the bacteria.

Haploinsufficiency

Haploinsufficiency occurs when a cell is incapable of producing the total level of a gene product (typically a protein). It happens only in diploid organisms, when only one of the gene copies is functional, while the other copy carries a mutation (e.g. a deletion in the gene itself).

In other words, if the normal phenotype requires protein production of both alleles and one is not functioning, there will only exist about 50% of the quantity necessary for the proper functioning of the cell, resulting in an abnormal phenotype, leading to disease (some cancers).