Intro to Chemotherapies

There is a lot of very complex chemistry in some of these drugs, but I am going to simplify the concepts. Instead of going over a 20 step process of how something is synthesized, I am just going to say it gets synthesized and a certain drug blocks this synthesis. I don't want to confuse or complicate the concepts here with a ton of complex chemistry. There are some concepts you will need to understand to be able to understand how some chemotherapy drugs work.

The first will be the basics of the Cell Cycle. You need to know the basics that the cell grows in stages from G1 to S phase to G2 phase and through mitosis. You will need to understand the basics of how the DNA is synthesized. Most Chemotherapy drugs will target rapidly dividing cells which are what cancer cells do. Some drugs target the process by which DNA gets copied. Understanding the basics of genetics of what the purines and pyrimidines are, how DNA is structured and how it gets copied. The last main concept will be to understand how Mitosis works with the Chromosomes. Some drugs target the process of mitosis to prevent rapidly dividing cells. When we get to these concepts, I will go over the basics of how they work.

The first key term we need to know about pharmacology is Mechanism of Action also known as Pharmacodynamics. This is how the drug actually works. What does it really do? All Chemotherapy drugs have one goal in their Mechanism of Action. All cancer cells grow and replicate at an alarming rate. Chemotherapy drugs target the many processes of the cell cycle or DNA synthesis to block cells from replicating. It is a very simple concept. The idea is most human cells do not go through mitosis very often. The cancer cells are going through mitosis very often. If you target cells that are going through the cell cycle and kill them, most of the time, you will be killing cancer cells. Yes, Chemotherapy targets and kills cells that are going through the growth cycle. This means any normal cells that try to go through the cell cycle will be collateral damage.

This leads to the many toxic side effects from chemotherapy. There are several groups of cells that suffer from chemotherapy. All our cells in our blood like Red Blood Cells, Platelets and White Blood Cells are made by the millions and billions per day. They all suffer from the toxic effects of chemotherapy. This often leads to cytopenias which is a fancy term for low cell counts. Chemotherapy patients will suffer from increased infections due to lower White cell counts. They can also suffer from Anemia or even increased bleeding times. The next cell that turns over often is the hair cells. Hair grows every day. Chemotherapy will disrupt and kill these cells. This often leads to hair loss with chemotherapy. The last major cell that suffers from the effects of chemotherapy is the GI tract. These cells turn over very frequently. This leads to some GI issues. One such issue is an inflamed GI tract. Some of these GI sores and inflammation can be very painful. Chemotherapy works, but it has many side effects. This leads to the concept of targeted therapies. These are designed to target only cancer cells by looking for things cancer cells have that healthy cells to not have.

Chemotherapies are actually groups of drugs that share many of the similar effects to block cells from dividing. A regimen is a set of chemotherapeutic drugs chosen from these many classes of drugs. Each chemotherapy regimen, for a specific cancer, might have different drugs from these classes in them. Sometimes, even different chemotherapy regimens will be different between patients with the same type of cancer. This will cover the classes of chemotherapy drugs. The Oncologist will pick drugs from these classes for each patient based on their cancer type. They will pick a group of drugs that they think will best help that specific patient for that specific cancer. Each patient is different and might have a different set of drugs in their regimen. Some regimens of drugs are used very commonly in specific cancer types such as CHOP or R-CHOP in Lymphomas.

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Anthracyclines

The first class of Chemotherapy drugs we will look at are a class of antibiotics called the Anthracyclines. You might be wondering why a class of antibiotics could work to fight cancer. We will look at the mechanism of action for this class of drugs. This is one of the top used chemotherapy drug classes. Forms of Doxorubicin and Daunorubicin are used in many types of cancer. The H in CHOP chemotherapy for Lymphoma stands for Hydroxydaunorubicin. They are a very effective class of drugs for treating cancer. They are typically administered by IV at specific times in the treatment cycle. They have a long laundry list of chemo related side effects. Their biggest concern is a side effect of Anthracycline related Cardiotoxicity. This makes them unable to be used in patients with any heart issues. Healthy patients will need constant monitoring for signs of cardiotoxicity.

So now that we know about this class of drugs, we will dig into how they work. If you think about what is similar between a bacteria and a human cell, what is the one key element? They both have double stranded DNA, and they both have to copy that DNA to replicate. The Anthracyclines have 3 ways in which they interfere with cell replication. The first is they intercalate into the DNA. This means the Doxorubicin or Daunorubicin will actually insert itself into the DNA. This interferes with the DNA synthesis and blocks DNA replication. The second way these drugs work is to block an enzyme called topoisomerase. This concept is a bit more complex if you haven't studied the process of DNA synthesis. When DNA gets copied, an enzyme called Helicase opens up the double strand of DNA. The DNA is a twisted pair. As the Helicase moves along, the DNA will attempt to unwind which will create tension on the twisted DNA. The topoisomerase precedes the Helicase along the DNA. When the tension gets too high, the topoisomerase will break the bonds of the DNA strands and unwind the tension before reattaching them again. The Anthracyclines will block topoisomerase which causes the tension of the DNA to increase until it breaks. Then you end up with tons of double stranded breaks at all these replication points across the chromosome. This causes p53 to trigger and initiate cell death. The last action they do is cause oxidative stress. If you studied immunology, you will understand oxidative stress and Radical Oxygen Species (ROS). These are created by chemical processes of the cells. The cell uses O2 (oxygen). In cellular processes like metabolism, oxygen ions (O2-) are created. These ionically charged Oxygens can cause damage. They play a large role in inflammation. This along with all the DNA damage causes these drugs to kill cancer cells.

As you can see, the class of Anthracyclines are very toxic to both cancer and healthy cells. They are also very effective which is why they are still widely used to treat cancer.

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Antimetabolites

Antimetabolites target cancer at the S phase of the cell cycle. To understand them, we will need to look at the metabolism of DNA nucleotides. The nucleotides used in the copying of DNA have to be synthesized. This is done in a chemical process called purine and pyrimidine metabolism. This is a very complex chemical process. We don't need to understand the process other than it happens. There are a bunch of enzymes and folate needed to synthesize these nucleotides. The antimetabolite drugs will target the creation and use of the nucleotide bases that are necessary for the copying of the DNA. There are a ton of these drugs, but I will go over a few very common drugs that demonstrate the different ways they target nucleotide metabolism. The purines are Adenine and Guanine. They have 2 rings. They are synthesized from the same process of metabolism. The pyrimidines are the single ring nucleotides that are Cytosine and Thymine in the DNA. The pyrimidines are metabolized in the same pathway. The Antimetabolites will be broken down into 4 types. They are folate synthesis inhibitors, purine synthesis inhibitors, pyrimidine synthesis inhibitors and analogs.

The first is the drugs that inhibit folate synthesis. The use of folic acid in metabolism of purine and pyrimidine synthesis makes drugs like Methotrexate kill cancer. Methotrexate blocks the synthesis of dihydrofolate into tetrahydrofolate which plays a key role in the creation of nucleotides. It also plays a key role in many other cells for growth like those blood cells. That leads to its use in many cancers like breast or lung cancer and inflammation disorders. The suppression of folate synthesis affects many cells. It brings with it all the common side effects of chemotherapy agents with cell counts, hair loss and GI toxicity. It has the additional concern of hepatotoxicity.

The set of drugs in this class will block the metabolism of purine or pyrimidine nucleotides. Some of them will block both pathways. There are a few common drugs used that work by this mechanism of action. Mercaptopurine is also known as 6-MP. This works by blocking an enzyme necessary for purine metabolism. It has many of the same antimetabolite effects and many of the same chemotherapy side effects. 5 Fluorouracil (5FU) is another antimetabolite which targets an enzyme in pyrimidine metabolism. This provides the same effects as other antimetabolites. This is a very commonly used antimetabolite drug for solid tumors like breast, cervical, colorectal and pancreatic. This drug has many of the common chemotherapy side effects from targeting cell division. It includes a special toxicity on the package for potential neurological damage.

The last drug I want to cover in this category is Gemcitabine which is used often. This is an example of an analog. It is a fake form of a nucleotide. When it enters the cell, it is modified so it can be used in the new strand of DNA. Because it's not a real nucleotide the DNA repair machinery won't be able to fix it. This leads to an unfixable DNA damage situation which arrests the cell division and causes the initiation of cell death by p53 activation.

Antimetabolites are a very common type of chemotherapy. They are sometimes used in combination with other antimetabolites or even other regimens of chemotherapy drugs. Very rarely is a chemo drug used alone. The major drawback of these drugs is they still affect all cells that go through the cell cycle. They cause a ton of collateral damage.

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Antimitotic Drugs

The antimitotic drugs are the Taxanes and the Vinca Alkaloids. These drugs target the cell cycle in its M phase targeting the process of mitosis itself. To understand how they work, we first need to understand the basics of mitosis. When the cells enter the M phase, the nucleus breaks down. Spindles will form and move to each side of the cell. The sister chromatids will line up at the center of the cell. The spindles will create Tubulin polymers to reach out and bind to 1 of each of the chromosome pairs. Then they pull on them and create tension like a game of tug of war. Once each spindle has a copy of each chromosome bound, the enzyme Seperase will cut the pairs of chromosomes apart. One copy of each chromosome will be pulled to each side of the cell. A new nucleus will form around each set of chromosomes and the cell will split in two.

The Taxanes work by disrupting the deformation of the Tubulin polymers. You might be thinking, "What is a polymer?" Let me explain. A polymer is basically a unit of something that gets strung together in a long chain. Like the beads on a necklace would be a polymer of beads. Tubulin is formed from 2 proteins called the Alpha and Beta protein that are combined together and repeated over and over again into long polymer chains. The Taxanes bind to the Beta Tubulin and stabilize it, preventing the deformation of the tubulin strands. This blocks the process of mitosis. This causes a problem with the cell and it undergoes cell death. There is a cell checkpoint at this stage. It is called the Spindle checkpoint. This is a set of proteins that verify that a single tubulin is attached to each chromosome before letting them split. Taxanes prevent cells from finishing the process of mitosis and blocks the cells which are going through the cell cycle. This brings with it many of the same side effects known with chemotherapy like suppression of the blood cells, hair loss and GI toxicity. The Taxanes were originally discovered from plants of the Yew. There are newer fully synthetic forms of taxanes. The 2 most common Taxanes are Docetaxel and Paclitaxel. These drugs are widely used in cancer chemotherapy regimens.

The other group of antimitotic drugs are the Vinca Alkaloids like Vincristine. As the taxane allows the formation of tubulin but blocks its breakdown, the vinca alkaloids prevent the formation of the tubulin at all. They have the same effect, but they just go about it differently. The Vinca Alkaloids work by blocking the formation of the Tubulin polymers. Vincristine is part of the Chemotherapy regimen for lymphoma. It is the O in CHOP going by its brand name Oncovin.

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Alkylating Agents

The last class of chemotherapy agents is known as the Alkylating Agents. This is a broader class of drugs that is known as the cytotoxic agents. These agents are designed to kill cells by damaging the DNA. If you recall the section on the DNA Damage Repair (DDR) pathway, when DNA is damaged, the pathway is triggered and p53 increases. This causes the cell cycle to stop and attempt repair of the DNA. If the damage is too great, the level of p53 will rise to the point where it will initiate cell death. That is the concept behind alkylating agents. They get into the DNA and cause massive damage to trigger the pathway that leads to cell death. There are several subclasses of Alkylating agents, but I am only going to look at 3 of them as we will see them so often in clinical trials. It will be very helpful when you see these drugs in treatments like cancer or even lymphodepletion to know what they do.

First we will look at the Nitrogen Mustard Agents. These get their name from their first use in Mustard Gas as a chemical warfare agent. They work by getting into the DNA and crosslinking the bases together. Mustard agents are complicated chemistry, but they are designed to do massive DNA damage and cause cell death by triggering the p53 activation. The most important Nitrogen Mustard drug we will deal with every day is Cyclophosphamide. This drug is used in the Lymphodepletion regimen of Fludarabine/Cyclophosphamide (Flu/Cy). Yes, you might have guessed it. Many of the same chemotherapy agents that treat cancer will wipe out the immune cells as they replicate very quickly. Some of these drugs like Busulfan, Cyclophosphamide and Fludarabine can also be used to wipe out immune cells or stem cells. Only Cyclophosphamide is a Nitrogen Mustard.

Busulfan is another type of Alkylating agent called Alkyl Sulfonates. Busulfan works by the same concept. It specifically cross links guanine bases. You will hear about Busulfan use in a lot in genetic therapies. It is used to deplete stem cells to remove them before transplant. It is used by companies doing stem cell therapies like CRISPR therapeutics for its Sickle Cell drug. It removes the bad stem cells before they put in the new ones.

The last group of Alkylating agents I want to talk about are the Platinum Chemotherapy drugs. They create platinum ions which cause cross linking of the DNA and result in the same damage. Like the other cytotoxic agents, they do massive DNA damage to initiate cell death. There are two very famous Platinum drugs with Cisplatin and Carboplatin. These drugs are used in Lung, Breast and Colon cancers. They are frequently used in combinations of other chemotherapy type drugs like the antimitotic or antimetabolites.

The clear example of a chemotherapy regimen is CHOP chemotherapy. This uses Cyclophosphamide as a DNA damaging agent with Daunorubicin as the anthracycline with Vincristine as the antimitotic drug. They are combined with Prednisone as it helps offset some of the inflammation side effects of the other drugs. These chemotherapy agents are quite toxic. They target the cell cycle to prevent cells from proliferation. This kills cancer cells, but it has very bad collateral damage in healthy tissues.

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