What is the toxicity of Hydroxyurea at the GI tract?
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 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 for years.
Interphase comprises of the G1 phase, during which the cell grows and performs its functions, the S phase, during which DNA is replicated, and the G2 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.
Okay, 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 gently snapping one strand, loosening the overwinding tension, and then patching it back up, tension free.
Okay, so topoisomerase inhibitors are meant to interfere with both types of DNA topoisomerases, called topoisomerase I and II.
Topoisomerase I cuts one of the two strands of the double-stranded DNA during replication, while Topoisomerase II cuts both strands.
If we disable these enzymes, DNA will overwind just like a rubber band, until it tears itself apart, leading to cell death.
They bind to and inhibit topoisomerase I and cause DNA damage during replication, leading to cell death.
Irinotecan is a prodrug, meaning that it needs to be metabolized into an active form within the liver before it can produce the desired effect.
The two most common side effects are myelosuppression, or depression of the bone marrow function and gastrointestinal problems like diarrhea, which is more common with irinotecan, but in general, these medications have fewer toxicities than most other anticancer agents.
These medications induce DNA breakage through the inhibition of topoisomerase II.
Moving on to the indications, these agents are used in: solid tumors, particularly in testicular and small cell lung cancer; in leukemia, which is a type of blood cancer primarily affecting stem cells in the bone marrow; and in lymphomas, which usually derive from lymphocytes in the lymph nodes.