Ribonucleotide reductase inhibitors

Definitions & Key takeaways

Ribonucleotide reductase inhibitors are a class of drugs that act by blocking an enzyme called ribonucleotide reductase. They are mainly used as anticancer agents that target DNA synthesis and cell growth. Ribonucleotide reductase inhibitors include drugs like hydroxyurea, fludarabine phosphate, and gemcitabine. Hydroxyurea is used for the treatment of myeloproliferative disorders and sickle cell disease; Fludarabine phosphate is used for leukemias and lymphomas; whereas gemcitabine is used for a variety of carcinomas and non-Hodgkin's lymphoma. Common side effects include myelosuppression, gastrointestinal disturbances, pulmonary toxicity, and liver toxicity.

Chapters:

Watch video only

Introduction0:00–0:18

Ribonucleotide reductase inhibitors, as their name implies, are a class of medications that act by blocking an enzyme called ribonucleotide reductase.
They are mainly used as anticancer agents that target a specific phase of the cell cycle. At a quick glance, the life of a cell - its cell cycle - has an interphase, made up of subphases G1, S, and G2, during which the cell is preparing for division; and mitosis, during which the cell actively divides.During the S phase, the cell performs DNA replication - which is when its 46 chromosomes are duplicated so that each daughter cell can get its own copy of the genetic material.

Physiology0:18–2:37

Now, a single chromosome is made up of a single DNA molecule that has two strands, which wrap around one another to form a double helix.
Each single strand of DNA is composed of a sequence of DNA nucleotides. Now, nucleotides are the building blocks of nucleic acids such as deoxyribonucleic acid, or DNA; and ribonucleic acid, or RNA.
The most basic structure of the nucleotide can be broken down into three subunits; a five carbon sugar, a phosphate group, and a nitrogenous base, also known as a nucleobase.
The five carbon sugar is either deoxyribose in DNA or ribose in RNA. Now, the nucleobases can be either pyrimidines or purines.
The 3 pyrimidine bases are cytosine, or C; thymine, or T, which is DNA specific; and uracil, or U, which is RNA specific.
There are also two purine bases, adenine, or A; and guanine, or G. Now, if we link up just the sugar and the nucleobase, we’ve got ourselves a nucleoside.
To make a nucleotide, all we’ve got to do is add a phosphate group to the 5th carbon of the sugar on a nucleoside. Okay, so in order to make DNA nucleotides we use RNA nucleotides.
RNA nucleotides are usually in the monophosphate form and we need to change them into the diphosphate form for DNA. So a cytoplasmic enzyme called ribonucleotide reductase, also known as ribonucleoside diphosphate reductase, will reduce the ribose within them into deoxyribose, creating deoxyribonucleotides, which then travel to the nucleus where DNA synthesis takes place.
Alright, now the cancer cells are going through the phases of the cell cycle like normal cells, but they divide much more frequently.

Mechanism of Action2:37–3:23

Therefore, cancer cells replicate their DNA all the time and they need more deoxyribonucleotides for this process. This makes them more sensitive to cytotoxic medications like the ribonucleotide reductase inhibitors, since they decrease the amount of available deoxyribonucleotides.
Ribonucleotide reductase inhibitors act in the S-phase of the cell-cycle, where the DNA replicates, and so they are cell-cycle specific.
There are also normal tissues that divide rapidly like bone marrow and hair follicles, which explains why these medications are more toxic to these tissues.

Hydroxyurea3:23–4:39

Okay, ribonucleotide reductase inhibitors are a diverse group of medications and include hydroxyurea, fludarabine phosphate, and gemcitabine.
Let’s start with hydroxyurea, also known as hydroxycarbamide, which is administered orally.Hydroxyurea binds to the iron molecules in ribonucleotide reductase, which prevents the enzyme from functioning.
Hydroxyurea is used for myeloproliferative disorders, a group of disorders characterized by proliferation of the bone marrow cells from the myeloid lineage, like chronic myelogenous leukemia and polycythemia vera.Hydroxyurea is also used for sickle cell disease because it stimulates the production of fetal hemoglobin, or HbF, although the exact mechanism remains uncertain.
Side effects include severe myelosuppression, presenting as leukopenia, macrocytic anemia, and occasionally thrombocytopenia.
Other side effects include gastrointestinal disturbances, pneumonitis, and mild skin reactions. Hydroxyurea is also associated with minimal teratogenic effects but its safety during pregnancy is not yet determined.

Fludarabine phosphate4:39–5:40

Next is fludarabine phosphate, which is a fluorinated and phosphorylated analog of the antiviral agent vidarabine. It can be administered either intravenously or orally.In the plasma, fludarabine phosphate is rapidly converted into fludarabine, but then it gets re-phosphorylated to a triphosphate derivative, which is the active form.Fludarabine triphosphate directly binds to and inhibits ribonucleotide reductase, and therefore blocks DNA synthesis.
Additionally, fludarabine triphosphate incorporates into DNA and blocks DNA polymerase which uses DNA as a template and starts adding nucleotides that are complementary to form a new DNA chain.
Moving onto indications, which include leukemias like chronic lymphocytic leukemia and low grade lymphomas. Now side effects include myelosuppression, fever, and gastrointestinal disturbances like nausea and vomiting.

Gemcitabine5:40–6:31

Let’s move on to gemcitabine, which is administered intravenously. When gemcitabine enters the cells, it undergoes phosphorylation and is converted into a diphosphate form which binds to and inhibits ribonucleotide reductase.
It also has a triphosphate form which can be incorporated into DNA and block DNA polymerase.Gemcitabine is indicated for a variety of carcinomas like pancreatic cancer, non-small cell lung cancer, ovarian cancer, bladder cancer, and for non-Hodgkin’s lymphoma.
Now, side effects include myelosuppression, pulmonary toxicity, which presents as pneumonitis, and a flu-like syndrome. Now, if gemcitabine is administered for a longer duration, it can lead to liver toxicity.

Memory Palace6:31–9:26

Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about ribonucleotide reductase inhibitors.
So first, let’s set the scene at the beach next to a nuclear power plant. The power plant tries to reduce their nuclear waste stockpile by dumping them into the sea, and the tide carries them to the shore.
This will help you remember we’re talking about the ribonucleotide reductase inhibitors.Now the first drug is hydroxyurea, so let’s have an ox drinking sea water to keep hydrated, while also urinating into the ocean.
There’s a pile of broken ox bones by him since a lot of his friends died drinking sea water, and this represents the main side effect which is bone marrow suppression.
In fact let’s put broken bones all along the beach since all 3 ribonucleotide reductase inhibitors share this side effect.
The bones by this ox have tiny trees sprouting out from them since they got extra nutrients from the ox’s urine, and they represent the main indication for hydroxyurea, which is myeloproliferative disorders.
There’s also a sickle sticking out from one of the trees which represents the other indication, sickle cell disease. For the other side effects, let’s have a pregnant lady reprimanding the ox and she’ll help you remember this medication is contraindicated during pregnancy.
She’s got a bad cough to represent the pulmonary toxicity and she also has a bad rash which is another side effect.Okay, so the owner of the ox is an Arabian man who flew in on a magic carpet and he represents fludarabine.
For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a giant crab. So let’s have him holding a bone club with little crabs in the marrow to represent leukemia.
Also, a crab is pinching a lymph node on his neck for lymphoma. He’s vomiting from the carpet to represent the GI side effects, and he’s also got a thermometer in his mouth since he thinks he might have a fever.
Okay, so trailing behind the man is his pet cheetah who’s wearing a gem-studded collar since he represents gemcitabine. The lady caretaker of the cheetah is pulling on its leash.
She’s holding a frying pan that contains an egg and some crabs, which represents pancreatic and ovarian cancer. Tied to the cheetah’s collar, there are two balloons; one looks like an inflated bladder and the other looks like a lung, and there are crabs on the balloon so you know they represent lung and bladder cancer.
Finally for side effects, the woman is wearing an antiviral flu mask and she’s coughing since gemcitabine causes flu-like symptoms and pneumonitis.
The cheetah is feasting on a big liver to help you remember that this medication could cause hepatotoxicity. ##SummaryAll right, as a quick recap… Ribonucleotide reductase inhibitors such as hydroxyurea, fludarabine phosphate and gemcitabine are used as anticancer agents.

Review9:26–10:28

They work by inhibiting ribonucleotide reductase and blocking the formation of deoxyribonucleotide. Since they prevent DNA synthesis, they act in the S phase and are cell-cycle specific.Hydroxyurea is used for the treatment of myeloproliferative disorders and for sickle cell disease.
Fludarabine phosphate is used for leukemias and lymphomas.Gemcitabine is used for a variety of carcinomas and for non-Hodgkin’s lymphoma.
A common side effect of these medications is myelosuppression. Hydroxyurea and fludarabine phosphate also cause GI disturbances.
Hydroxyurea and gemcitabine cause pulmonary toxicity like pneumonitis. Long-term treatment with gemcitabine causes liver toxicity.
pneumonitis long-term treatment with gemcitabine causes liver toxicity But wait there's more Here's a mind map of all the mnemonics go ahead and pause the video so you can test yourself to see what you remember Stay tuned for

Mind Map10:28–10:40