A 25-year-old man comes to the office for the evaluation of left testicular mass. He first noticed the mass 3 weeks ago when he was taking a shower. It is painless and hard in consistency. Past medical history is unremarkable. Family history is significant for lung cancer in the patient’s father. Vitals are within normal limits. Physical examination shows firm ovoid left testes with a rubbery enlargement. The right testicle appears normal. Ultrasound of the testes shows a solid left testicular mass. A left orchiectomy is performed. A postoperative histologic and molecular analysis of the testes shows that the cancer cells are sensitive to etoposide. Which of the following best describes the mechanism of action of this drug?

Topoisomerase inhibitors

Definitions & Key takeaways

Topoisomerase inhibitors are a group of medications used in cancer chemotherapy that target the enzyme called DNA topoisomerase I or II, which is involved in DNA replication and transcription.

Topoisomerase inhibitors work by preventing the enzyme from unwinding DNA strands during replication or transcription, which leads to the accumulation of DNA damage and cell death. Examples include irinotecan and topotecan which inhibit topoisomerase I; and etoposide and teniposide which inhibit topoisomerase II.

Topoisomerase inhibitors are used to treat various types of cancer, such as colon cancer, leukemia, ovarian, and small-cell lung cancer. Common side effects of topoisomerase inhibitors include fatigue, gastrointestinal problems like diarrhea, hair loss, anemia, and increased risk of infection. Some patients may also experience more severe side effects, such as cardiac toxicity or secondary malignancies.

Chapters:

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Introduction0:00–0:22

Topoisomerase inhibitors as their name implies are a class of medications that act by blocking an enzyme called topoisomerase.

They are mainly used as anticancer agents that target specific phases of the cell cycle. An interesting fact about these agents is that they are natural products, meaning they are extracted from roots, plants or trees.

But first things first, the cell cycle refers to the events that somatic cells, which includes all of the cells in our body, except the reproductive cells go through from the moment they're formed until the moment they divide into two identical daughter cells.

Physiology0:22–2:06

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 for years. Now, the cell cycle could be divided into two phases.

Interphase and mitosis interphase comprises of the G one phase during which the cell grows and performs its functions. The S phase during which the DNA is replicated in the G two phase during which the cell grows again before entering mitosis or the M phase 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.

Ok. So, during DNA replication, we unzip the double helix with the enzyme DNA helicase.

And this creates a replication fork with the two prongs of the fork represented by the two strands that are separated from one another.

Now as DNA helicase unzips, the DNA, the segments of DNA ahead of it start to overwind, meaning the double helix becomes more tightly wound, overwinding of the DNA can slow down replication.

So the enzyme DNA topoisomerase works ahead of DNA helicase to loosen up the tight DNA coils. It achieves this by snapping one strand, loosening the overwinding tension and then patching it back up tension free.

So topoisomerase inhibitors are meant to interfere with both types of DNA topoisomerases called topoisomerase one and two topoisomerase.

Mechanism of Action2:06–2:58

One cuts one of the two strands of the double stranded DNA during replication. While topoisomerase two cuts both strands.

If we disable the enzymes, DNA will overwind just like a rubber band until it tears itself apart leading to cell death. Since cancer cells in general proliferate faster than healthy cells, they undergo DNA replication more frequently and are more prone to the DNA damage caused by topoisomerase inhibitors.

All right. Now, topoisomerase inhibitors are cell cycle specific or CCS agents and they are the most active during the late S and early G two phases of the cell cycle.

Ok. Let's start with camptothecins like iron Tekin and Topotecan, which are isolated from the stems of the camptothecin tree, also called happy tree cancer tree or tree of life.

Camptothecins2:58–4:00

They bind to and inhibit topoisomerase one and cause DNA damage during replication leading to cell death. Iran Oin is a prodrug, meaning that it needs to be metabolized into an active form within the liver before it can produce the desired effect.

In terms of elimination. Irinotecan is excreted through the bile and feces.

While topotecin is excreted through the kidneys. So the dose should be reduced in people with impaired renal function.

Now, irinotecan is used in metastatic colon cancer and topotecin is used for the treatment of advanced ovarian cancer and for small cell lung cancer.

The two most common side effects are myelosuppression or depression of the bone marrow function and gastrointestinal problems like diarrhea.

But in general, these medications have fewer toxicities than most other anticancer agents. All right.

Next, we have podophylla toxins like opposite and teniposide, which are derived from the mandrake root or podophyllum peltatum.

Podophyllotoxins4:00–4:51

These medications induce DNA breakage through the inhibition of topoisomerase. Two elimination of teniposide and opus side is mainly through the kidneys, which again means that the dosage needs to be reduced in people with renal problems.

Moving on to the indications. These agents are used in solid tumors, particularly in testicular and small lung cancer in leukemia, which is a type of blood cancer, primarily affecting stem cells in the bone marrow and lymphomas which usually derive from lymphocytes in the lymph nodes.

Ok. Now, common toxicities include myelosuppression, gastrointestinal disturbances and alopecia or hair loss.

Memory Palace4:51–7:05

Now, let's make a simple and fun mnemonic that'll help you efficiently memorize these pharmacology facts about topoisomerase inhibitors.

So let's start in a garden to remind us that topoisomerase inhibitors are natural plant derived products. The garden is split into two parts by a fence.

On one side, we can put topoisomerase one inhibitors. The camptothecins, which is represented by one happy tree.

And on the other side, we can put topoisomerase two inhibitors, the podophylla toxins, which are represented by two giant mandrakes.

Ok. On the camptothecin side, let's have 22 cans since these medications end in to can.

Now one is lifting an iron dumbbell for iron O tec and the other is wearing a top hat for Topotecan for indications. Let's use crabs to represent cancer since in the zodiac cancer is a giant crab.

So there's a crab pinching the weightlifting toucans. But to help you remember, it's used for colon cancer.

The top hat toucan is guarding two eggs with little crabs on them to represent ovarian cancer. On his hat, there's another crab carrying a tiny lung for small cell lung cancer under the tree.

Let's have a dog digging up some broken bones for bone marrow suppression. Unfortunately, the bones are very dirty and they gave him diarrhea.

Ok. Let's move on to the podophyllotoxin side of the garden.

Here, we'll have Poseidon guarding the mandrakes and he represents the medications that end with pos he's wearing a top hat for oppose side while holding a tennis racket for teniposide.

Ok. For indications he's sitting on a crab statue made of solid stone.

Since these medications treat solid tumors, there's a tiny crab on his head that's carrying a tiny lung for small cell lung cancer.

Next, Poseidon is wearing a jockstrap to help you remember, testicular cancer instead of a trident, he's holding a giant bone club with little crabs in the marrow which represents leukemia.

There's also a little crab pinching a lymph node on his neck. For lymphomas, the side effects are very similar to camptothecins.

So let's use the dog digging up the broken bones for bone marrow suppression. This dog is vomiting to represent gi distress.

And finally, let's give the dog a bald spot for alopecia. All right, is a quick recap.

Review7:05–7:42

Topoisomerase inhibitors are a class of plant derived medications that are used in the treatments of various types of cancer.

They are cell specific agents and work by causing DNA damage by disabling the DNA topoisomerase one or two irinotecan and topotecan inhibit topoisomerase one and they are used in colon ovarian and small cell lung cancer.

In contrast, etoposide and teniposide inhibit topoisomerase two and they are used in testicular and small cell lung cancer, leukemia, and lymphoma.

But wait, there's more, here's a mind now with all the mnemonics, go ahead and pause the video so you can test yourself and see what you remember.