Anti-Cancer Drugs

Cells are remarkable things. Scientists estimate that nearly two trillion of your cells divide every day, producing identical daughter cells with exactly the same DNA sequence as the original cell. At least, that is what is supposed to happen. However, sometimes DNA isn't copied exactly. The genetic sequence changes and this can cause the new daughter cell to behave differently. It may start dividing rapidly and uncontrollably. This is known as cancer.

However, there are many drugs that we have at our disposal to help fight against rogue cancerous cells. We will focus on one of them in particular: cisplatin.

• This article is about the anti-cancer drug cisplatin.
• We'll start by providing an overview of anti-cancer drugs on general before focusing on cisplatin.
• We'll look at its structure and mechanism of action before exploring some of its side effects.

What is cancer?

As we defined at the start, cancer is a disease characterised by rapid, uncontrolled cell division. Healthy cells divide regularly as part of a process called the cell cycle. They have many security measures that help regulate this, telling them when to divide and when to go about other cellular activities. Cells are limited to how many times they can divide before they die. However, in cancerous cells these security measures are either missing or faulty. Instead, the cell divides rapidly and uncontrollably.

The uncontrolled cell division is caused by mutations in the cell's DNA. Mutations come from many different sources. In fact, DNA naturally mutates all the time - it is just that most of these mutations have no effect whatsoever on the cell. Only occasionally does a mutation cause a harmful effect such as cancer. You can also get mutations from carcinogenic substances such as x-rays and other radiation.

Because cancerous cells divide so rapidly, they grow faster than normal cells. They can then invade and destroy surrounding healthy tissue, including organs. This is why cancer is life-threatening.

What are anti-cancer drugs?

Using anti-cancer drugs to treat cancers is known as chemotherapy. 28 percent of all cancer patients undergo chemotherapy as part of their treatment regime. It can have up to a 90 percent success rate against some forms of cancer.

Different anti-cancer drugs have different mechanisms and methods of treatment. depending on their classification. They also all have different side effects and dosages, and attack separate types of cancer. Doctors need to take all these factors into consideration when prescribing anti-cancer drugs.

Classification of anti-cancer drugs

Let's explore some of the different types of anti-cancer drugs:

• Alkylating agents work by interfering with the cancerous cell's DNA replication. They do this by cross-linking DNA strands or matching up DNA base pairs abnormally.
• Antimetabolites interfere with the enzymes involved in DNA synthesis.
• Hormonal agents alter the amounts of hormones in and around the cancerous cell, which affects its cellular division.
• Plant alkaloids bind to certain proteins during specific stages of the cell cycle, causing the cancerous cell to enter mitotic arrest and die.

Cisplatin

Cisplatin is a particular anti-cancer drug. To be exact, it is a type of alkylating agent. For the rest of this article, we're going to look specifically at how it works in treating cancers.

Cisplatin as an anti-cancer drug

As we mentioned above, cisplatin is an example of an anti-cancer drug, or more specifically, an alkylating agent. It treats cancer by stopping DNA replication, which prevents the cell from dividing.

Structure

Cisplatin has the molecular formula $\left[\mathrm{Pt}{\left(\mathrm{Cl}\right)}_2{\left({\mathrm{NH}}_3\right)}_2\right]$. It is an example of a complex ion with two chloride ligands and two ammonia ligands bonded to a central platinum atom.

By looking at the term ‘cisplatin’, we can visualise its structure. Cisplatin is actually one of a pair of two optical isomers, molecules with the same structural formulae but different arrangements of groups around a central atom. In the cis- isomer, the chloride ligands are next to each other. In the trans- isomer, they are opposite one another.

Fig. 1 - Cisplatin and transplatin. The chloride ligands are circled to help you identify their position

The shape of cisplatin is a square planar. The cis- structure and the square planar shape of cisplatin give it the correct geometry that is fundamental to its function.

Mechanism of action

The structure of cisplatin plays an important role in how it acts as an anti-cancer agent.

When cisplatin is in the body, water displaces one of the chloride ligands in a ligand substitution reaction called aquation. This happens because the concentration of water around the complex cisplatin ion is much higher than the concentration of chloride ions.

Aquation makes it easier for cisplatin to then bind to DNA bases - in particular, guanine. A nitrogen atom in guanine donates its lone pair of electrons to the platinum ion in cisplatin, forming a dative covalent bond. This gets rid of the newly-acquired water ligand in another ligand substitution reaction.

The same substitution then happens to the other chloride ligand, but this time the chloride ligand is replaced by a nitrogen atom from guanine on the opposite DNA strand. The binding to guanine cross-links the two DNA strands and distorts the shape of the DNA. This prevents the cell from replicating its DNA. The cell tries to fix the DNA damage using repair mechanisms but ultimately is unsuccessful. This triggers apoptosis, cell death.

Fig. 2 - Cisplatin binds to guanine bases on opposite DNA strands

Side effects

Cisplatin isn't selective. It binds to DNA in all cells, not just cancer cells. However, because cancer cells replicate much more rapidly than healthy human cells, cisplatin's effect on them is much greater. But other frequently replicating cells like hair follicle cells are also affected and killed off. This is why chemotherapy patients sometimes experience hair loss. Other side effects include nausea, vomiting, and fatigue.

However, it is important to remember that chemotherapy can be extremely beneficial, and for some people, it is their best shot at treating cancer. Cisplatin in particular has a 90 percent success rate against testicular cancer. Although the side effects are unpleasant, they can be managed through drugs such as antiemetics. However, it should always be up to the patient as to whether they want to undergo any sort of cancer treatment or not.