Anticancer Drugs - Part II: Antimetabolites
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Questions and Answers

What is the primary mechanism by which antimetabolites function?

  • They act as false substrates for nucleotide biosynthesis enzymes (correct)
  • They directly cause DNA damage
  • They inhibit protein synthesis
  • They enhance the synthesis of cellular metabolites

Which class of nucleotide do purine antagonists specifically inhibit?

  • Cytidine and Uridine
  • ADP and GDP
  • ATP and GTP
  • AMP and GMP (correct)

What significant side effect is associated with the use of mercaptopurine?

  • Severe diarrhea
  • Uric acid toxicity (correct)
  • Liver damage
  • Nausea and vomiting

How does allopurinol affect the efficacy of mercaptopurine?

<p>It increases the levels of active 6-thioinosinic acid (A)</p> Signup and view all the answers

Mercaptopurine is classified as what type of agent?

<p>An immunosuppressive agent (B)</p> Signup and view all the answers

What is the role of hypoxanthine-guanine phosphoribosyl-transferase (HPGRT) in relation to mercaptopurine?

<p>It converts mercaptopurine to an active form (C)</p> Signup and view all the answers

In which condition is mercaptopurine primarily used?

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

Which of the following statements about mercaptopurine is false?

<p>It competes with uric acid for renal excretion (C)</p> Signup and view all the answers

What is the primary action of Vinca Alkaloids in the treatment of cancer?

<p>Inhibit polymerization of microtubules (C)</p> Signup and view all the answers

Which characteristic of Estramustine phosphate (EMP) distinguishes it from its parent compound estramustine?

<p>EMP is a prodrug with estrogenic effects (B)</p> Signup and view all the answers

Why is Estramustine phosphate not used to treat estrogen-dependent tumors?

<p>It selectively targets prostate tissue (A)</p> Signup and view all the answers

What effect does Paclitaxel have on the microtubules during tumor treatment?

<p>It stabilizes microtubules and prevents their breakdown (A)</p> Signup and view all the answers

What type of drug is Estramustine phosphate (EMP) described as?

<p>A dual agent with cytostatic and hormonal effects (D)</p> Signup and view all the answers

What mechanism leads to the effectiveness of EMP against prostate cancer?

<p>Disassociation of MAP-4 from microtubules (C)</p> Signup and view all the answers

Which of the following is a common side effect associated with Estramustine phosphate?

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

Which statement correctly describes the pharmacological profile of Estramustine phosphate?

<p>Its phosphate ester enhances water solubility and IV administration (C)</p> Signup and view all the answers

What is azathioprine primarily used for?

<p>Immunosuppression in organ transplantation and autoimmune diseases (A)</p> Signup and view all the answers

How is azathioprine converted to 6-mercaptopurine?

<p>By being attacked by glutathione (B)</p> Signup and view all the answers

What is the role of thymidylate synthase in pyrimidine metabolism?

<p>It is the rate-limiting enzyme in dTMP synthesis (A)</p> Signup and view all the answers

What is the impact of the electron-withdrawing ability of the heterocyclic group on azathioprine?

<p>It accelerates the conversion to mercaptopurine (A)</p> Signup and view all the answers

Which of the following drugs is metabolized by dihydropyrimidine dehydrogenase (DPD)?

<p>5-Fluorouracil (B)</p> Signup and view all the answers

What is the significance of replacing the fluorine atom in 5-fluorouracil with an ethinyl moiety?

<p>It enhances drug stability and therapeutic index (D)</p> Signup and view all the answers

Which statement accurately describes thioguanine?

<p>It is ineffective when combined with allopurinol (B)</p> Signup and view all the answers

What adverse effect is associated with inhibiting thymidylate synthase in rapidly dividing cells?

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

What is the major use-limiting side effect of anthracyclines?

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

How does Dexrazoxane function in the context of anthracycline treatment?

<p>Decreases the cardiac toxicity by chelating iron (A)</p> Signup and view all the answers

What mechanism does Mitomycin C utilize to exert its effects?

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

What advantage does the enhanced stability of the quinone ring in Mitoxantrone provide?

<p>Decreased production of highly toxic hydroxyl radicals (B)</p> Signup and view all the answers

Which cancer treatments is Mitoxantrone commonly used for?

<p>Hormone-refractory prostate cancer and acute non-lymphocytic leukemia (C)</p> Signup and view all the answers

Which cancers is 5-fluorouracil (5-FU) primarily used to treat palliatively?

<p>Colorectal, Breast, Stomach, and Pancreatic (C)</p> Signup and view all the answers

What is the primary mechanism by which 5-fluorouracil exerts its anticancer effect?

<p>Acting as a competitive inhibitor of thymidylate synthetase (B)</p> Signup and view all the answers

What is the result of dihydropyrimidine dehydrogenase (DPD) metabolism of 5-fluorouracil?

<p>Formation of neurotoxic 5-fluoro-5,6-dihydrouracil (A)</p> Signup and view all the answers

Which of the following improves the therapeutic index of 5-fluorouracil?

<p>5-ethynyluracil (D)</p> Signup and view all the answers

What is the primary role of Tegafur in cancer treatment?

<p>It is a prodrug converted into 5-fluorouracil. (D)</p> Signup and view all the answers

How does capecitabine function in the body?

<p>It is absorbed intact and rapidly converted to 5-FU. (B)</p> Signup and view all the answers

What is the mechanism of action for Methotrexate as a folic acid antagonist?

<p>It competes with dihydrofolic acid for dihydrofolate reductase. (C)</p> Signup and view all the answers

What effect does the inhibition of dihydrofolate reductase (DHFR) have on thymidylate synthase?

<p>It causes a decrease in dihydrofolate levels and feedback inhibition of thymidylate synthase. (C)</p> Signup and view all the answers

What is the primary mechanism of action of Nelarabine in cancer treatment?

<p>Inhibiting ribonucleotide reductase and DNA synthesis (A)</p> Signup and view all the answers

Which of the following anticancer agents is indicated for treating hairy cell leukemia?

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

Which agent is known to inhibit ribonucleotide reductase by chelation with Fe2+?

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

What characteristic of Cladribine, Clofarabine, and Fludarabine makes them resistant to deamination by adenosine deaminase?

<p>C2 halogen substitution (B)</p> Signup and view all the answers

What is the role of tubulin during mitosis?

<p>To form microtubules for chromosome segregation (B)</p> Signup and view all the answers

Which anticancer drug is known to cause chain termination during DNA synthesis?

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

For which type of cancer is Fludarabine primarily used?

<p>Chronic lymphocytic leukemia (D)</p> Signup and view all the answers

What is a significant property of Clofarabine that enhances its stability?

<p>The presence of an arabinose fluorine group (A)</p> Signup and view all the answers

Flashcards

Antimetabolites

Compounds that prevent the biosynthesis or utilization of normal cellular metabolites.

Purine Antagonists

Antimetabolites that inhibit the synthesis of purine-based nucleotides AMP and GMP.

Mercaptopurine

A prodrug that, after transformation in the body, inhibits de novo purine synthesis.

6-Mercaptopurine

A specific form of mercaptopurine, often used to treat cancers.

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Uric acid toxicity

A side effect of mercaptopurine caused by its conversion to an inactive form (6-thiouric acid) by xanthine oxidase.

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Xanthine oxidase

Enzyme that converts mercaptopurine to an inactive form, potentially causing uric acid toxicity.

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Allopurinol

A medication that inhibits xanthine oxidase, reducing uric acid toxicity from mercaptopurine.

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Immunosuppressive agent

An agent (like Mercaptopurine) that suppresses the body's natural immune response.

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Antimitotic Agents

Drugs that stop cell division by interfering with the cell's ability to make the structural support for cell division

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Vinca Alkaloids

Antimitotic agents that block microtubule polymerization

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Estramustine Phosphate

A dual-action drug that disrupts microtubule structure & promotes estrogen-like effects

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Microtubule Disruption

The process where microtubules are broken down, affecting cell division

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Taxanes

Antimitotic agents inhibiting microtubule depolymerization

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Estrogen-like effect

Estramustine's secondary role of mimicking estrogen effects

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Prodrug

A medication that isn't active itself, requiring conversion by the body to become effective.

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Toxicity Concerns EMP

Estramustine phosphate (EMP) can lead to thromboembolic and cardiovascular complications like pulmonary embolism or heart issues.

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Azathioprine's action

Azathioprine is a prodrug that's slowly converted to 6-mercaptopurine, providing sustained activity. Glutathione helps in this conversion.

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Azathioprine Use

Used to suppress the immune system in organ transplants and autoimmune diseases.

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Thymidylate Synthase

The enzyme that makes dTMP (a building block for DNA). Inhibiting this enzyme stops DNA synthesis.

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5-Fluorouracil (5-FU)

An anticancer drug that inhibits thymidylate synthase, interfering with DNA synthesis.

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5-FU Metabolism

5-FU is changed by the body into an inactive form by dihydropyrimidine dehydrogenase (DPD).

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Mercaptopurine elimination

Mercaptopurine quickly leaves the body as it is not a prodrug

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Thioguanine use

Used in the orall treatment of non-lymphocytic leukemias and acute leukemias especially in combination with cytarabine

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5-FU therapeutic improvement

Replacing the F in 5-FU with an ethyl group improves its effectiveness by 2-4 times.

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5-FU Mechanism

5-FU is bioactivated to 5F-dUMP, inhibiting thymidylate synthetase, an enzyme essential for DNA synthesis. This disrupts cancer cell growth.

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5-FU Deactivation

Dihydropyrimindine dehydrogenase (DPD) inactivates 5-FU by converting it to 5-fluoro-5,6-dihydrouracil and F--alanine, which are neurotoxic.

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Tegafur

Tegafur is a prodrug that is converted into 5-FU in the body. It's used in combination with cisplatin to treat various cancers.

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Anthracycline toxicity

The main side effect of anthracyclines is cardiac toxicity due to the formation of damaging free radicals.

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Capecitabine

Capecitabine is another prodrug of 5-FU that's absorbed through the stomach and then metabolized to 5-FU through a three-step process.

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Dexrazoxane's role

Dexrazoxane (a cardioprotective agent) reduces the toxicity of anthracyclines by binding to iron ions, preventing the formation of cytotoxic free radicals.

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Mitoxantrone's mechanism

Mitoxantrone, an anthracenedione, inhibits topoisomerase II by binding to the DNA backbone, interfering with DNA replication.

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Floxuridine

Floxuridine (FUDR) is a nucleoside analog of 5-FU that's converted to 5-F-dUMP. It's administered by infusion for GI cancer treatment.

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Methotrexate Mechanism

Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase (DHFR), leading to a buildup of DHF. This indirectly inhibits thymidylate synthase, hindering DNA synthesis.

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Mitoxantrone and cardiac toxicity

Mitoxantrone has a stable quinone ring that resists conversion into harmful hydroxyl radicals by enzymes, leading to low cardiac toxicity.

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Methotrexate's Other Target

Methotrexate also inhibits glycine amide ribonucleotide (GAR) transformylase, an enzyme crucial for purine nucleotide synthesis.

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Mitomycin C's mechanism

Mitomycin C, a drug isolated from bacteria, utilizes bioreductive alkylation, a two-step process involving reduction and alkylation, to damage DNA.

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Nelarabine

A prodrug of Ara-G that increases water solubility and is used for acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

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Ara-G's Transformation

Nelarabine is converted by adenosine deaminase (ADA) to Ara-G and then to the active form Ara-GTP.

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Ara-GTP's Action

Ara-GTP inhibits ribonucleotide reductase (RNR) and DNA synthesis by chain termination.

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2-Haloadenosine Analogs

Cladribine, Clofarabine, and Fludarabine are examples of these analogs, which are resistant to deamination by ADA.

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Cladribine (2-CdA)

Used for hairy cell leukemia, Cladribine inhibits RNR and DNA polymerase, preventing cancer cells from multiplying.

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Clofarabine (Cl-F-Ara-A)

A stable drug used for acute lymphoblastic leukemia, containing a fluorine group for better stability and reduced degradation.

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Fludarabine (F-Ara-A)

Used for chronic lymphocytic leukemia, Fludarabine acts by inhibiting RNR and DNA polymerase, similar to other 2-haloadenosine analogs.

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Hydroxyurea

Oral medicine that inhibits ribonucleotide reductase by chelating with Fe2+, reducing deoxyribonucleotides required for DNA synthesis.

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Study Notes

Anticancer Drugs - Part II

  • Antimetabolites: These compounds prevent normal cellular metabolism or biosynthesis. They are structurally similar to normal metabolites, acting as antagonists. Classified by the nucleotide they inhibit.

Types of Antimetabolites

  • Purine Antagonists: Inhibit purine-based nucleotides like AMP and GMP. 6-Mercaptopurine (6-MP) is an example.

  • Pyrimidine Antagonists: Inhibit pyrimidine-based nucleotides like dTMP. Examples include 5-fluorouracil (5-FU) and related drugs.

    • 5-FU: Metabolized into an active form that inhibits thymidylate synthetase.

  • DNA Polymerase Inhibitors: Directly or indirectly inhibit DNA polymerase. Examples include cytarabine (ara-C).

  • Folate Antagonists: These inhibit the synthesis of the cofactor for thymidylate synthesis. Examples include methotrexate.

Specific Antimetabolites

  • 6-Mercaptopurine (6-MP): A prodrug converted in the body to a potent inhibitor of purine synthesis. Used to treat acute leukemia and pediatric lymphoma. It's important to understand the drug's metabolic pathway and potential side effect, especially uric acid toxicity.

  • Azathioprine: An imidazolyl derivative that is a prodrug of 6-MP. It's valuable because it provides a more sustained activity compared to 6-MP, slowing conversion to active drug. Used in organ transplantation and autoimmune diseases

  • Thioguanine: Administered orally, inhibiting the synthesis of purine nucleotides. Used in treating certain leukemias, particularly important when combined with other drugs like cytarabine.

  • Cytarabine (ara-C): A pyrimidine analog that is effective against leukemia. Important for understanding its conversion to triphosphate and subsequent miscoding effects that inhibit chain elongation in DNA & RNA synthesis

  • Gemcitabine: Another pyrimidine analog, also used in various cancers, such as breast, pancreatic and non-small cell lung cancers. Important aspects are its conversion to triphosphate analogue and its effects on DNA/RNA synthesis and cell death.

  • Nelarabine: A prodrug that is converted to an active form that inhibits ribonucleotide reductase (RNR) and DNA synthesis by chain termination. It increased water solubility is important.

  • Cladribine, Clofarabine, Fludarabine: These are 2-haloadenosine analogs designed to be resistant to deamination by adenosine deaminase. Used in specific cancers.

  • 5-Fluorouracil (5-FU): A pyrimidine analog used in many cancers. Is metabolized by dihydropyrimidine dehydrogenase (DPD) into an inactive form, but this metabolic step can be improved via 5-ethynyluracil which improves therapeutic index

  • Fluoxuridine: Converted into active form 5-FdUMP, inhibiting thymidylate synthetase.

  • Hydroxyurea: Inhibits ribonucleotide reductase, disrupting DNA synthesis and decreasing the level of deoxyribonucleotides. Used in melanoma and ovarian cancer.

Antimitotic Agents

  • Vinca Alkaloids (Vinblastine, Vincristine): Inhibit microtubule polymerization, interfering with mitosis. Important in various lymphomas and leukemias.

  • Estramustine Phosphate: A dual cytostatic and hormonal agent; it acts on both mitotic and hormone pathways.

  • Taxanes (Paclitaxel, Docetaxel): Stabilize microtubules, inhibiting depolymerization, which interferes with mitotic spindle formation preventing cell division.

  • Mitoxantrone: An anthracenedione that intercalates with DNA and interferes with topoisomerase II preventing DNA and RNA synthesis

  • Mitomycins: Act by bioreductive alkylation of DNA. Interfere with cell division.

Other

  • Anthracyclines (Doxorubicin, Daunorubicin, Idarubicin): Intercalate with DNA, causing single and double-strand breaks. Important consideration is the role of iron and its contribution to the drug's cardiotoxicity and the role of Dexrazoxane.

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Anticancer Drugs Part II 2024 PDF

Description

This quiz delves into the second part of anticancer drugs focusing on antimetabolites. Learn about their classifications, including purine and pyrimidine antagonists, DNA polymerase inhibitors, and folate antagonists. Test your understanding of specific drugs like 6-Mercaptopurine and 5-Fluorouracil.

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