Antimetabolites
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Questions and Answers

What is the general function of antimetabolites?

  • They accelerate cell division in malignant cells.
  • They enhance the creation of DNA metabolites.
  • They block the synthesis of DNA. (correct)
  • They promote the formation of new RNA.

In which phase of the cell cycle do most antimetabolites exert their toxic effects?

  • S phase (correct)
  • G1 phase
  • G2 phase
  • M phase

Which of the following is a pyrimidine base?

  • Adenine
  • Arginine
  • Cytosine (correct)
  • Guanine

Which nitrogenous base is found in RNA, but not in DNA?

<p>Uracil (A)</p> Signup and view all the answers

What are the purine bases?

<p>Adenine and Guanine (A)</p> Signup and view all the answers

What is formed when a nitrogenous base is attached to a ribose sugar and a phosphate group?

<p>Nucleotide (A)</p> Signup and view all the answers

Which of the following contains Cytosine?

<p>Cytidine (A)</p> Signup and view all the answers

What does ribonucleotide reductase do?

<p>Removes a hydroxyl group from ribonucleotides. (A)</p> Signup and view all the answers

Which enzyme adds a base to PRPP?

<p>HGPRT (C)</p> Signup and view all the answers

Azathioprine is converted into what active drug?

<p>6-MP (B)</p> Signup and view all the answers

Azathioprine and 6-MP are commonly used for which of the following?

<p>Immunosuppression (B)</p> Signup and view all the answers

What is a major adverse effect of Azathioprine and 6-MP?

<p>Myelosuppression (B)</p> Signup and view all the answers

Allopurinol and febuxostat inhibit which enzyme?

<p>Xanthine Oxidase (A)</p> Signup and view all the answers

What happens when allopurinol or febuxostat are co-administered with Azathioprine or 6-MP?

<p>Increased risk of adverse effects (C)</p> Signup and view all the answers

Which of the following drugs inhibits ribonucleotide reductase?

<p>Hydroxyurea (C)</p> Signup and view all the answers

What is a major clinical use of Hydroxyurea?

<p>Sickle cell anemia (A)</p> Signup and view all the answers

Which of the following directly inhibits DNA Synthesis?

<p>Antimetabolites (D)</p> Signup and view all the answers

Which of these drugs mimics purines or pyrimidines?

<p>Azathioprine (A)</p> Signup and view all the answers

What is a common side effect of drugs that disrupt DNA synthesis?

<p>Myelosuppression (C)</p> Signup and view all the answers

What is monitored in oncology patients due to the risk of neutropenia?

<p>Absolute Neutrophil Count (ANC) (B)</p> Signup and view all the answers

What type of anemia is commonly caused by drugs discussed in this module?

<p>Megaloblastic anemia (D)</p> Signup and view all the answers

What is a characteristic finding in a peripheral smear of a patient with megaloblastic anemia?

<p>Hypersegmented neutrophils (A)</p> Signup and view all the answers

Cytarabine mimics which nucleotide?

<p>Cytidine (C)</p> Signup and view all the answers

What is true of Cytarabine's effectiveness?

<p>Effective in leukemia and lymphomas (A)</p> Signup and view all the answers

Cladribine is a purine analog that mimics:

<p>Adenosine (A)</p> Signup and view all the answers

Cladribine is the drug of choice for:

<p>Hairy cell leukemia (D)</p> Signup and view all the answers

What is special about Cladribine among the Antimetabolites?

<p>It is cell cycle nonspecific (C)</p> Signup and view all the answers

What condition is Methotrexate used to treat by reducing or eliminating long-term steroid use?

<p>Autoimmune diseases (D)</p> Signup and view all the answers

Methotrexate mimics the structure of:

<p>Folate (C)</p> Signup and view all the answers

What is a major side effect associated with Methotrexate, especially at high dosages?

<p>Myelosuppression (D)</p> Signup and view all the answers

Methotrexate inhibits which enzyme?

<p>Dihydrofolate reductase (A)</p> Signup and view all the answers

What nucleotide's formation is blocked by Methotrexate?

<p>Thymidine (B)</p> Signup and view all the answers

Which drug can reverse the myelosuppressive effects of Methotrexate?

<p>Leucovorin (A)</p> Signup and view all the answers

What enzyme does Methotrexate inhibit?

<p>Dihydrofolate reductase (D)</p> Signup and view all the answers

Thymidylate Synthase requires what co-factor to carry out its reaction?

<p>N5,N10 Tetrahydrofolate (D)</p> Signup and view all the answers

What enzyme converts Dihydrofolate into Tetrahydrofolate?

<p>Dihydrofolate reductase (D)</p> Signup and view all the answers

What is a common side effect of Methotrexate, characterized by mouth soreness?

<p>Mucositis (A)</p> Signup and view all the answers

Which of the following is a potential, but rare, side effect of Methotrexate, especially in patients taking low doses for immunosuppression?

<p>Methotrexate-induced lung injury (D)</p> Signup and view all the answers

Besides malignancies, what other condition it Methotrexate used to treat?

<p>Auto-immune diseases (D)</p> Signup and view all the answers

Which nitrogenous base does 5-Fluorouracil (5-FU) mimic in structure?

<p>Uracil (C)</p> Signup and view all the answers

5-FU inhibits which enzyme?

<p>Thymidylate synthase (A)</p> Signup and view all the answers

What type of cell death is associated with 5-FU?

<p>Thymineless death (B)</p> Signup and view all the answers

What type of cancer is 5-FU commonly used to treat?

<p>Colorectal cancer (D)</p> Signup and view all the answers

What is a rare, but notable, cardiovascular side effect of 5-FU?

<p>Coronary vasospasm (B)</p> Signup and view all the answers

Which nitrogenous bases does 6-Mercaptopurine (6-MP) mimic?

<p>Hypoxanthine and Guanine (C)</p> Signup and view all the answers

Which enzyme adds 6-MP to PRPP (phosphoribosyl pyrophosphate)?

<p>HGPRT (D)</p> Signup and view all the answers

What is the mutant form of a purine created when 6-MP is added to PRPP?

<p>Thioinosinic acid (B)</p> Signup and view all the answers

What cellular process does Thioinosinic acid inhibit?

<p>Purine Salvage Pathway (D)</p> Signup and view all the answers

Flashcards

Antimetabolites

Chemotherapy medication that inhibits the production of DNA's building blocks

S Phase

The phase of the cell cycle where DNA replication happens.

Pyrimidines

Nitrogenous bases with a single-ring structure

Examples of Pyrimidines

Cytosine, Thymine, and Uracil.

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Purines

Nitrogenous bases with a double-ring structure.

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Examples of Purines

Adenine and Guanine.

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Nucleotide

A nitrogenous base attached to a ribose sugar and at least one phosphate group.

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Ribonucleotide Reductase

Enzyme that converts ribonucleotides to deoxyribonucleotides.

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PRPP Structure

A molecule structurally similar to a nucleotide, lacking a base; accepts a base via HGPRT.

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HGPRT Function

Enzyme that adds guanine or hypoxanthine to PRPP, creating GMP or IMP respectively.

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6-Mercaptopurine (6-MP) Mechanism

Mimics hypoxanthine/guanine; HGPRT adds it to PRPP, forming a mutant nucleotide that inhibits DNA synthesis.

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Azathioprine

A pro-drug converted to 6-MP in the body, exerting immunosuppressive effects.

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Azathioprine/6-MP Uses

Immunosuppression, steroid-sparing, IBD, and preventing organ rejection.

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Azathioprine/6-MP Adverse Effects

Myelosuppression, abnormal LFTs, GI upset.

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Xanthine Oxidase

Enzyme that converts xanthine to uric acid; inhibited by allopurinol and febuxostat.

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Allopurinol/Febuxostat + Azathioprine/6-MP Interaction

Leads to increased Azathioprine/6-MP toxicity due to decreased drug breakdown.

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6-Thioguanine MOA

Mimics purines; decreases IMP, AMP, and GMP levels, inhibiting DNA synthesis.

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Hydroxyurea Mechanism

Inhibits ribonucleotide reductase, blocking the formation of deoxyribonucleotides and DNA synthesis.

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Myelosuppression

A common side effect of DNA synthesis-disrupting drugs, affecting rapidly dividing bone marrow cells.

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Neutropenia

Reduced neutrophil count, increasing risk of bacterial infections.

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Megaloblastic Anemia

Anemia with large red blood cells (increased MCV) and hypersegmented neutrophils, caused by defective DNA production

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Cytarabine (Ara-C)

Chemotherapy drug; pyrimidine analog mimicking cytidine, inhibits DNA polymerase.

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Cytarabine Adverse Effects

Inhibition of DNA polymerase, myelosuppression, and potential neurotoxicity at high doses.

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Cladribine

Purine analog mimicking adenosine, highly toxic to lymphocytes.

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Hairy Cell Leukemia

A rare form of leukemia that Cladribine is typically used to treat.

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Cladribine Adverse Effects

Cell cycle non-specific, causes myeolosuppresion.

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Methotrexate

Mimics folate, inhibits dihydrofolate reductase, decreases DNA synthesis.

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Dihydrofolate Reductase

Enzyme inhibited by methotrexate, important for folate metabolism.

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Tetrahydrofolate (THF) Importance

Synthesis of tetrahydrofolate is blocked, which is needed for DNA, RNA and protein synthesis.

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Thymidylate Synthase

Enzyme that converts dUMP to dTMP, requiring N5,N10-THF.

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THF

N5,N10-tetrahydrofolate.

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Methotrexate Mechanism

Blocks Thymidine synthesis.

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Methotrexate Uses

Malignancies, autoimmune diseases via immunosuppression

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Methotrexate-Induced Myelosuppression

A significant adverse effect of Methotrexate, especially at high doses, but can be reversed with leucovorin.

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Leucovorin

Folinic acid that reverses myelosuppression caused by methotrexate, converting to THF without dihydrofolate reductase.

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Methotrexate-Induced Mucositis

Mouth soreness, a common side effect of Methotrexate that causes damage to the GI epithelium leading to pain and bacterial growth.

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Methotrexate-Induced Lung Injury

A rare but serious side effect of Methotrexate, potentially leading to pulmonary fibrosis if untreated.

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5-Fluorouracil (5-FU)

A drug that mimics uracil and inhibits thymidylate synthase, leading to thymineless death in cells.

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Mechanism of 5-FU

Inhibition of thymidylate synthase due to mutant Uridine monophosphate.

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Thymineless Death

Cells cannot synthesize Thymidine.

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Leucovorin with 5-FU

It enhances 5-FU effects by increasing the binding of mutant Uridine monophosphate to thymidylate synthase.

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5-FU Clinical Uses

Colorectal, breast, and pancreatic cancers

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5-FU CNS Side Effects

Cerebellar ataxia and encephalopathy.

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5-FU-Induced Coronary Vasospasm

A rare but significant side effect of 5-FU, leading to angina and EKG changes.

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6-Mercaptopurine (6-MP) Mimics

It mimics hypoxanthine and guanine.

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HGPRT Role

An enzyme that adds 6-MP to PRPP, forming Thioinosinic acid.

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Thioinosinic acid Action

Inhibits purine salvage pathway, decreases inosine monophosphate, adenosine monophosphate and guanosine monophosphate levels.

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Study Notes

  • Antimetabolites are chemotherapy drugs used to treat malignancy, blocking the formation of DNA components and thus DNA synthesis.
  • Most antimetabolites are cell cycle specific, affecting primarily the S phase when DNA is synthesized.

Biochemistry Review

  • DNA and RNA contain nitrogenous bases, classified as pyrimidines (one ring) or purines (two rings).
  • Pyrimidines include Cytosine, Thymine (DNA only), and Uracil (RNA only).
  • Purines include Adenine and Guanine.
  • A nucleoside is a nitrogenous base attached to a ribose sugar, while a nucleotide includes a phosphate group.
  • Pyrimidine and purine nucleotides are named similarly to their corresponding bases (e.g., Cytidine contains Cytosine).
  • Ribonucleotides contain a hydroxyl group, used in RNA, while deoxyribonucleotides lack this group, used in DNA.
  • Deoxyribonucleotides are synthesized from ribonucleotides via ribonucleotide reductase, which removes the hydroxyl group.

Common Side Effects

  • Antimetabolites target rapidly dividing cells, including bone marrow precursor cells, leading to myelosuppression.
  • Myelosuppression results in megaloblastic anemia, thrombocytopenia, and leukopenia.
  • Absolute Neutrophil Count (ANC) is monitored in oncology patients; levels below 500 indicate neutropenia, increasing infection risk.
  • Megaloblastic anemia is characterized by reduced hematocrit, increased MCV (large cells), and hypersegmented neutrophils on peripheral smear.
  • Besides chemotherapy drugs, megaloblastic anemia can also be caused by B12 or Folate deficiencies.

Cytarabine (Ara-C)

  • Pyrimidine analog, mimics deoxycytidine, inhibiting DNA polymerase when incorporated into DNA.
  • Effective in treating leukemia and lymphomas.
  • Adverse effects include myelosuppression, nausea, vomiting, and high doses can cause neurotoxicity (peripheral neuropathy, confusion, cerebellar ataxia).

Cladribine

  • Purine analog, mimics adenosine, highly toxic to lymphocytes.
  • Drug of choice for hairy cell leukemia.
  • Cell cycle nonspecific, with primary adverse effect of myelosuppression.

Methotrexate

  • Mimics Folate, inhibiting dihydrofolate reductase, which is crucial for folate metabolism.
  • Blocks tetrahydrofolate synthesis, required for DNA, RNA, and protein synthesis.
  • Prevents the formation of thymidine, a nucleotide necessary for DNA synthesis.
  • Used in malignancies (IV), and autoimmune diseases (oral) as a steroid-sparing agent.
  • Can induce pregnancy abortion (ectopic pregnancies).
  • Adverse effects include Myelosuppression (reversed by leucovorin, folinic acid), mucositis (mouth soreness), hepatitis, GI upset, and rarely, methotrexate-induced lung injury that may progress to pulmonary fibrosis.

5-Fluorouracil (5-FU)

  • Mimics uracil, a pyrimidine, but with a fluorine atom at the 5 position.
  • Converted in cells to 5-fluoro-deoxyuridine monophosphate, which inhibits thymidylate synthase, blocking thymidine formation and causing "Thymineless death".
  • Leucovorin enhances the effects of 5-FU, unlike methotrexate.
  • Major drug for colorectal cancer, also used for breast and pancreatic cancers, and topically for basal cell skin cancer.
  • Adverse effects include myelosuppression, nausea, vomiting, diarrhea, mucositis, CNS effects (cerebellar ataxia, encephalopathy), and coronary vasospasm.

6-Mercaptopurine (6-MP)

  • Mimics the purine bases hypoxanthine and guanine.
  • Added to PRPP by HGPRT, forming Thioinosinic acid, a mutant purine.
  • Inhibits purine salvage pathway, decreasing levels of IMP, AMP, and GMP.

Azathioprine

  • Prodrug converted to 6-MP.
  • Used for immunosuppression (steroid-sparing agent), inflammatory bowel disease, preventing organ rejection, and treating autoimmune diseases.
  • Adverse effects include myelosuppression, abnormal LFTs, and GI upset.
  • Metabolized by xanthine oxidase; concurrent use of allopurinol or febuxostat (xanthine oxidase inhibitors) can increase its effects and toxicity.

6-Thioguanine

  • Mimics the purines hypoxanthine and guanine; similar mechanism to 6-MP.
  • Inhibits DNA synthesis by decreasing cellular levels of IMP, AMP, and GMP.

Hydroxyurea

  • Inhibits ribonucleotide reductase, blocking the conversion of ribonucleotides to deoxyribonucleotides, thus inhibiting DNA synthesis.
  • Orally bioavailable.
  • Adverse effect is myelosuppression.
  • Used in myeloproliferative disorders and sickle cell anemia (increases fetal hemoglobin levels, mechanism unclear).

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Description

This flashcard covers antimetabolites, their mechanisms of action, and clinical uses. It includes the function of antimetabolites, their effects on the cell cycle, and specific examples of antimetabolites. It also covers drug interactions and adverse effects.

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