DNA alkylating medications

Definitions & Key takeaways

Alkylating medications are a type of chemotherapy drugs used against cancer, which work by damaging the DNA of cancer cells. They disrupt the structure of DNA by adding an alkyl group to the guanine base, which prevents cancer cells from growing and dividing. There are many different alkylating agents which can be given alone or in combination with other drugs. Examples of DNA alkylating medications include Cyclophosphamide, Busulfan, and Melphalan.

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Introduction0:00–0:16

DNA alkylating medications are a class of drugs that are mainly used as anticancer agents. They disrupt the structure of DNA by adding an alkyl group to the guanine base and can affect all phases of the cell cycle.

Physiology0:16–1:24

Alright, the cell cycle refers to the events that somatic cells, which includes all of the cells in our bodies except the reproductive cells, go through from the moment they’re formed until the moment they divide into two identical daughter cells.
This cycle varies in length depending on the type of cell. For rapidly dividing cells, like skin cells, it takes less than a day, whereas for other cells, like liver cells, the cell cycle can last years.
Now, the cell cycle can be divided in two phases: interphase and mitosis. Interphase comprises of the G1 phase, during which the cell grows and performs its cell functions, the S phase, during which DNA is replicated, and the G2 phase, during which the cell grows again before entering mitosis.
Mitosis can be broken down into prophase, metaphase, anaphase, and telophase, during which the replicated DNA divides equally for the two daughter cells, and ends with cytokinesis, which is when the cell membrane actually divides to form the two new cells.
There’s also a G0 phase which is an extended G1 phase where the cell is resting and not actively preparing to divide. Alright, now imagine a cancer cell.

Pathology1:24–2:47

This cell is going through the phases of the cell cycle without regulation, and its DNA also replicates more frequently and with less error-correcting than healthy cells.
Therefore, it’s more sensitive to DNA damage. Here’s a DNA base, guanine.
Alkylating agents attach an alkyl group at the number 7 nitrogen atom of guanine. Based on their mechanism of action, alkylating agents are characterized as monofunctional, or bifunctional.
When monofunctional alkylating agents attach an alkyl group to guanine, repair enzymes recognize there’s something wrong, so they attempt to replace the alkylated bases and cause fragmentation of the DNA, or DNA strand breakage.
When this section of the DNA is repaired, abnormal base pairing could result, like having a thymine paired up with guanine instead of the usual cytosine.
Eventually, the DNA damage, that is caused by the monofunctional alkylating agents, can potentially lead to carcinogenesis, or development of cancer cells, or it can result in cell death.
Now, the primary mechanism by which bifunctional alkylating agents cause DNA damage is the crosslinking of DNA. In this process, an alkylating agent that has two DNA binding sites causes two guanine bases to link together, forming a covalent bond, leading to the formation of cross-bridges.
Cross-linking prevents DNA from being separated for replication or transcription, eventually resulting in cell death. DNA alkylating medications are cell cycle-nonspecific agents, meaning they act on tumor cells during all phases of the cell cycle, including the resting G0 phase.

Nitrogen Mustards2:47–5:17

Okay, let’s start with the nitrogen mustards, which include cyclophosphamide, mechlorethamine, and ifosfamide. Nitrogen mustards are related to phosgene, the lethal ‘mustard gas’ that was used during World War I, but it’s also the first intravenous chemotherapy treatment for cancer.
Alright, now these agents are prodrugs, meaning that they are administered in an inactive form which needs to be metabolized into an active form by the liver cytochrome P450 enzymes.
Now moving onto the indications, cyclophosphamide and ifosfamide can be used in various types of cancers. They are used against leukemias, which are a type of cancer that affect the cell in the bone marrow that eventually becomes white and red blood cells, and lymphomas, which are cancers of the immune cells in the lymph nodes.
It can also treat other solid tumor cancers like ovarian and breast cancer. Apart from the treatment of cancer, high doses of cyclophosphamide is immuno ablative and can be used to treat small-vessel vasculitis like granulomatosis with polyangiitis and microscopic polyangiitis, and also in polyangiitis nodosa, which is a medium-vessel vasculitis.
Finally, cyclophosphamide can be used for progressive or refractory cases of systemic lupus erythematosus, an autoimmune disease affecting multiple organs, and for multiple sclerosis, a demyelinating disease of the central nervous system.
In terms of toxicity, all alkylating agents depress bone marrow function and can cause aplastic anemia. However, the most dangerous thing is the risk of developing leukemia or other malignancies after prolonged use.
Other common toxicities with these medications include hair loss, gastrointestinal disturbances, and depression of gametogenesis, which can cause infertility.
Finally, alkylating medications are teratogens, meaning that they disrupt fetal development and can lead to birth defects.
Now, nitrogen mustards specifically, can cause syndrome of inappropriate antidiuretic hormone secretion, which can be shortened to SIADH.
This is where an inappropriate presence of antidiuretic hormone causes water retention and euvolemic hyponatremia. Cyclophosphamide can also cause bladder cancer and hemorrhagic cystitis, which is very common.

Busulfan5:17–6:17

The toxic metabolite of cyclophosphamide that is responsible for hemorrhagic cystitis is acrolein. However, there’s also good news.
Hemorrhagic cystitis can be prevented by increasing fluid intake and administering compounds that are sulfhydryl donors, like mesna or sodium-2-mercaptoethane sulfonate.
Alright, let’s move on to busulfan. Unlike cyclophosphamide, busulfan does not require any bioactivation in order to fight tumor cells.
It’s highly toxic to the bone marrow through the release of methyl radicals, but it’s not that toxic to the other organs.
Therefore, it’s one of the most potent agents against leukemia, and is especially effective against chronic myelogenous leukemia, or CML, a type of blood cancer that affects granulocytes.
It decreases the formation of granulocytes and platelets at low dosage, and red cells in higher dosage. Now busulfan is used before bone marrow transplant as a part of myeloablative conditioning, where both the cancer cells and healthy bone marrow are destroyed to make room for the new bone marrow.

Nitrosoureas6:17–6:45

Now the side effect is of course, the suppression of the bone marrow, leading to decreased platelets, red blood cells, and white blood cells.
Other less frequent toxicities include: pulmonary fibrosis, where excess collagen or scar tissue form in the interstitial tissue of the lung; and hyperpigmentation, or darkening of the skin.
Okay, now nitrosoureas, which include carmustine and lomustine, also require activation in the liver by the cytochrome P450.

Memory Palace6:45–9:25

They are highly lipid-soluble medications, meaning they can cross the blood-brain barrier and that’s why they are primarily used to treat brain tumors, like glioblastoma multiforme.
However, when they are also neurotoxic and can cause convulsions, seizures, and ataxia, or poor coordination of muscle movements.
Finally, there’s procarbazine, whose exact mechanism is still unknown. It’s used to treat Hodgkin lymphoma, as well as brain tumors.
Moving onto side effects, procarbazine can cause suppression of the bone marrow, leading to decreased blood cell counts, but it can also cause leukemia, where there’s increased white blood cell count.
Other side effects include pulmonary toxicity, and disulfiram-like reactions, also known as alcohol intolerance. In other words, individuals taking alcohol while on first generation sulfonylureas can experience hangover-like symptoms, such as nausea, vomiting, flushing, dizziness, and headache.
Finally, when taking procarbazine, you should avoid certain foods that contain the molecule tyramine, such as chocolate, cheese, and wine, because they can trigger the release of catecholamines.
This can lead to a hypertensive crisis, and that’s called a tyramine-induced hypertensive crisis. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about DNA alkylating medications.
So first, let’s imagine we are in a store that sells alkaline batteries. The first customer is a cyclops for cyclophosphamide.
He’s wearing a mechanic’s outfit to represent mechlorethamine. He wants to buy batteries for his knock-off I-fone, to represent ifosfamide.
He lets loose a mighty fart cloud that’s mustard-yellow in color, to help you remember these are nitrogen mustards. For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a giant crab.
So for leukemia, let’s have the cyclops holding a bone club in one hand, with little crabs in the marrow. Next, he’s got a large lymph node on his neck with a crab pinching it for lymphomas.
A crab is also in his chest pocket pinching inappropriately to help you remember the solid tumors like breast cancer. For the non-cancer indications, let’s use the cyclop’s pet wolf, which represents lupus.
On its back, are multiple scarecrows for multiple sclerosis. The wolf has bulging arteries on its body to represent the different vasculitides that cyclophosphamide can also treat.
For side effects, the cyclops is wearing a diaper for the syndrome of inappropriate antidiuretic hormone. There’s a big bloody spot on it, to help you remember hemorrhagic cystitis.

Review9:25–10:12

Next, let’s move on to busulfan, which is a businessman who’s also a sultan. He’s riding a camel that’s just a skeleton to help you remember it’s very toxic to the bone marrow.
The camel represents CML, but it’s also effective against other leukemias. Finally, the fact that it’s all bones will help you remember busulfan is used before bone marrow transplants.
For side effects, a spider built a web on the camel’s chest to represent pulmonary fibrosis, and the skull is scorched black for hyperpigmentation.
Okay, the next group of medications are the nitrosoureas like carmustine and lomustine. So let’s have a nitro powered Mustang-limo crash through the store.
The VIP is a crab with a giant brain, since their main indication is brain cancers. These drugs can cause CNS toxicity like seizures, which is why the driver crashed.

Mind Map10:12–12:26

Okay, so let’s use the couple who owns the store to represent the side effects common to all the DNA alkylating agents. One of them is a balding man, which represents hair loss.
The man is saying he wants a vasectomy to help you remember infertility. His wife is pregnant, to help you remember these medications are teratogenic, and she’s so angry she snapped a bone in half, to represent bone marrow suppression.
Finally, the arguing couple is surrounded by crabs, since all the alkylating agents increase the risk of developing malignancies.
The last medication is Procarbazine, which is a pro-wrestler caribou. We don’t know his identity and this will help you remember that the mechanism is unclear.
For indications, he’s beating up a hedgehog with crab claws to represent Hodgkin lymphoma, and another crab with a big brain for brain tumors.
There’s a table behind them full of snacks for after the match, and this is where we can put the side effects. First there’s some wine and cheese on a blood pressure cuff for tyramine induced hypertensive crisis, there’s a bottle of beer for disulfiram-like reaction, and a pair of lung shaped balloons with a skull on it for pulmonary toxicity.
All right, as a quick recap…DNA alkylating agents are a class of medications used primarily in the treatment of cancer. They are cell cycle-nonspecific agents, meaning they target all phases of the cell cycle.
Cyclophosphamide and other nitrogen mustards can treat leukemias, lymphomas, and solid tumor malignancies. Busulfan targets bones and is primarily used for leukemias and myeloablative conditioning before bone marrow transplant.
Nitrosoureas, cross the blood-brain barrier and are mainly used in brain cancers. Side effects of all alkylating agents include myelosuppression, hair loss, gastrointestinal disturbances, and after prolonged use, sterility and high risk for developing leukemia or other malignancies.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits. you can test yourself and see what you remember