DNA Topoisomerase Inhibitors
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Questions and Answers

Camptothecin derivatives inhibit topoisomerases by which mechanism?

  • Competitive inhibition of the ATP binding site.
  • Causing double-stranded breaks in the DNA.
  • Enhancing the rate of cleavage and preventing re-ligation. (correct)
  • Inhibiting DNA-topoisomerase binding.

Which of the following is a key distinction between type I and type II topoisomerases concerning their mechanism of action?

  • Type I topoisomerases cause single-strand breaks, while type II cause double-strand breaks. (correct)
  • Type I topoisomerases are not present in tumors, while type II are.
  • Type I topoisomerases require ATP hydrolysis, while type II do not.
  • Type I topoisomerases cause double-strand breaks, while type II cause single-strand breaks.

Why are topoisomerases considered important targets for chemotherapeutic agents?

  • They protect tumor cells from the effects of other chemotherapeutic agents.
  • They are generally downregulated in tumor cells, preventing DNA replication.
  • They are only present in healthy cells, making them ideal for selective targeting.
  • They are generally present at elevated levels in tumors, making them a vulnerable target. (correct)

Novobiocin and coumermycin inhibit Type II topoisomerases, which act through what mechanism?

<p>Preventing ATP-hydrolysis, which drives enzymatic action. (C)</p> Signup and view all the answers

Which of the following best describes the ‘cleavage complex’ formed by topoisomerase inhibitors?

<p>A complex where the enzyme is bound to DNA, preventing re-ligation of the DNA strands. (D)</p> Signup and view all the answers

Which mechanism describes how dexrazoxane inhibits topoisomerase II?

<p>Inhibiting ATP hydrolysis and DNA release. (B)</p> Signup and view all the answers

What critical function does camptothecin perform in its mechanism of action?

<p>It prevents DNA religation, forming a stable ternary complex. (C)</p> Signup and view all the answers

What limits the clinical use of camptothecin?

<p>Low solubility in aqueous environments. (C)</p> Signup and view all the answers

What modification enhances the pharmaceutical properties of camptothecin?

<p>Substitution of the A ring increases solubility. (D)</p> Signup and view all the answers

Irinotecan is a prodrug that requires activation to its active form, SN-38. Which enzyme is primarily responsible for this conversion?

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

Irinotecan is used in combination with other drugs for the treatment of colon cancer. Which chemotherapy regimen includes irinotecan?

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

What is the role of CYP3A4 in irinotecan metabolism?

<p>It metabolizes irinotecan to an active compound. (D)</p> Signup and view all the answers

Which specific type of cancer is Topotecan used to treat?

<p>Ovarian and lung cancer (B)</p> Signup and view all the answers

Camptothecin is derived from which natural source?

<p>The bark and stem of Camptotheca acuminata (C)</p> Signup and view all the answers

What is the ultimate cellular consequence of the DNA strand breaks caused by camptothecin?

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

Etoposide works by which of the following mechanisms?

<p>Forming a stable ternary complex with topoisomerase II and DNA, leading to DNA breaks. (A)</p> Signup and view all the answers

Which of the following describes the primary mechanism of resistance to etoposide?

<p>Enhanced efflux of the drug via ABC transporters. (D)</p> Signup and view all the answers

What phase of the cell cycle is primarily affected by Etoposide?

<p>Late S/Early G2 Phase (A)</p> Signup and view all the answers

Which of the following is a common clinical use of etoposide?

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

Vincristine and vinblastine disrupt microtubules by which mechanism?

<p>Binding to tubulin dimers and blocking microtubule assembly. (D)</p> Signup and view all the answers

Why does vincristine commonly cause peripheral neuropathy?

<p>It disrupts axonal transport by disrupting microtubules in neural cells. (B)</p> Signup and view all the answers

How does paclitaxel affect microtubule dynamics?

<p>It stabilizes microtubule polymers, inhibiting cell replication. (D)</p> Signup and view all the answers

What is the primary mechanism of action of docetaxel?

<p>Stabilizing microtubules, similar to paclitaxel. (A)</p> Signup and view all the answers

Which of the following is a key difference between vinblastine and vincristine in terms of their clinical use and side effects?

<p>Vinblastine is commonly associated with myelosuppression, while vincristine is commonly associated with peripheral neuropathy. (B)</p> Signup and view all the answers

What is the source of paclitaxel?

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

Which of the following bests describes what a microtubule stabilizer does?

<p>Enhances polymerization of tubulin. (C)</p> Signup and view all the answers

What is the mechanism of action of Noscapine?

<p>Sigma opioid receptor agonist. (B)</p> Signup and view all the answers

What is the relationship between ABC transporters and drug resistance?

<p>Cancer cells can upregulate ABC transporters to pump drugs out, leading to resistance. (D)</p> Signup and view all the answers

Etoposide is derived from what source?

<p>May-apple (<em>Podophyllum peltatum</em>) (C)</p> Signup and view all the answers

Which of the following is NOT an application of Paclitaxel according to the text?

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

Flashcards

Topoisomerases

Enzymes that manipulate the supercoiling of DNA during replication and transcription.

Type I Topoisomerases

Enzymes that create single-strand breaks in DNA, changing its supercoiling without ATP.

Type II Topoisomerases

Enzymes that create double-strand breaks in DNA, typically requiring ATP.

Topoisomerase inhibitors

Drugs that inhibit topoisomerase action, preventing DNA re-ligation and leading to strand breaks.

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Topoisomerase poisons

A class of inhibitors that lock topoisomerases in a cleavage complex, preventing DNA repair.

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Camptothecin

A topoisomerase I inhibitor that prevents religation, causing DNA strand breaks and apoptosis.

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Ternary complex

A stable structure formed by camptothecin, topoisomerase I, and DNA.

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Adverse drug reactions

Negative side effects caused by drugs like camptothecin.

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Irinotecan

A semisynthetic analogue of camptothecin used for colon cancer treatment.

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Topotecan

Another analogue of camptothecin used to treat ovarian and lung cancer.

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Prodrug activation

The conversion of a prodrug (like irinotecan) to its active form (SN-38).

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CYP3A4 metabolism

Enzyme that metabolizes irinotecan into its active metabolite.

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UDP glucuronosyltransferase

An enzyme involved in the metabolism of irinotecan.

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Camptotheca acuminata

Tree from which camptothecin is isolated, used in Traditional Chinese Medicine.

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Downregulated

Decreased expression of a gene or protein.

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Upregulated

Increased expression of a gene or protein.

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Etoposide

A drug that inhibits topoisomerase II, causing DNA breaks.

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Topoisomerase II

An enzyme that helps manage DNA supercoiling during replication.

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Myelosuppression

Reduction in bone marrow's ability to produce blood cells.

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Vinca alkaloids

Class of anti-cancer drugs that disrupt microtubule formation.

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Paclitaxel

A stabilizer that enhances tubulin polymerization for cancer therapy.

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Docetaxel

A drug similar to Paclitaxel with higher affinity for tubulin.

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Microtubules

Cytoskeletal components that support cell structure and transport.

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Antimicrotubular agents

Medications that disrupt microtubule functions.

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Glutathione conjugation

A phase 2 metabolic process that can contribute to drug resistance.

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ABCs

ATP-binding casette transporters that can pump out drugs.

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Resistance mechanisms

Changes that allow cancer cells to evade treatment.

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Cell cycle phases

Different stages of cell division: G1, S, G2, M.

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Study Notes

DNA "Cutters" - Topoisomerases Inhibitors

  • Camptothecin and derivatives are inhibitors of DNA topoisomerases
  • Anthracyclines are also inhibitors of DNA topoisomerases
  • Podophyllotoxin derivatives are DNA topoisomerase inhibitors

DNA Topoisomerases

  • Crucial in DNA replication and RNA transcription
  • Type I topoisomerases cause single-strand breaks in DNA, changing its supercoiling
  • Type II topoisomerases cause double-strand breaks in DNA
  • Topoisomerases are often elevated in tumors

Topoisomerase Inhibitors

  • Inhibit DNA topoisomerase activity, impacting various cellular processes
  • Some inhibitors prevent the re-ligation step of DNA after a break
  • Competing for ATP binding stalls DNA hydrolysis
  • Inhibiting DNA-topoisomerase binding disrupts the enzymes
  • Prevent ATP hydrolysis and DNA release

Camptothecin

  • Forms a stable ternary complex with topo I-DNA
  • Intercalates between DNA bases
  • Causes DNA strand breaks, leading to apoptosis
  • Exhibits strong activity in preclinical trials
  • Low solubility in water

Camptothecin Analogues

  • Structurally modified derivatives of camptothecin
  • Irinotecan and Topotecan are notable examples
  • Irinotecan is a prodrug that is metabolised to SN-38
  • Topotecan primarily used for ovarian and lung cancer

Irinotecan (CPT-11) Metabolism

  • Metabolised by CYP3A4 to active SN-38
  • Further metabolised to an inactive form via glucoronidation by UGT1A1
  • Resistance to Irinotecan can stem from reduced UGT1A1 function which hinders metabolism from SN-38 to its inactive form
  • Resistance can also arise due to increased expression of CYP3A4.

Cytochrome P450

  • Irinotecan is also inactivated by P450 enzymes (CYP3A4)

Anthracyclines - Mechanism of Action

  • Inhibit topoisomerase II, leading to DNA strand breaks
  • Intercalates with DNA, causing partial unwinding
  • Generates free radicals that damage DNA, and cell membranes
  • Important antitumor antibiotics like Doxorubicin and Daunorubicin.

Anthracycline Toxicity

  • Myelosuppression (bone marrow suppression)
  • Mucositis (oral inflammation)
  • Cardiac toxicity, potentially delayed.
  • Dexrazoxane can reduce adverse cardiovascular effects and may reduce cardiac toxicity

Resistance to Anthracyclines

  • Increased expression of DNA repair enzymes contributes significantly
  • Variations in drug efflux transporters can contribute to drug resistance.

Podophyllotoxin Derivatives

  • Semi-synthetic glycoside derivatives of podophyllotoxin
  • Etoposide and Teniposide are examples
  • These accumulate better in cells compared to other compounds

Etoposide (VP-16)

  • Non-intercalating topoisomerase II inhibitor
  • Forms a stabilized ternary complex with topoisomerase II and DNA
  • Leads to single and double-strand DNA breaks

Etoposide - Clinical Use

  • Used to treat testicular cancer, lung cancer, acute myeloid leukemia

Etoposide Resistance

  • Enhanced efflux of the drug from cells
  • Decreased binding to topoisomerase II
  • Increased glutathione conjugation

Antimicrotubular Agents

  • Vinca alkaloids (Vinblastine, Vincristine) and Taxanes (Paclitaxel, Docetaxel)
  • These compounds affect microtubules function hence cell division
  • Microtubules are important components of the cytoskeleton; involved in mitosis, cell structure, organelle transport

Vinca Alkaloids

  • Vincristine and Vinblastine bind to tubulin
  • Destabilize microtubules and inhibit cell division.

Clinical Activity of Vinca Alkaloids

  • Vincristine is effective against leukemia, lymphomas and solid tumors
  • Vinblastine effective against Hodgkin's Lymphoma and non-small cell lung cancer.

Paclitaxel (Taxol)

  • Tubulin stabilizer
  • Prevents microtubule depolymerization
  • Effective against ovarian, breast, and lung cancers

Docetaxel (Taxotere)

  • Tubulin binder with higher affinity compared to paclitaxel
  • Effective against ovarian and breast cancers.

Noscapine

  • Isoquinoline alkaloid
  • Found in opium latex
  • Investigational for use in the treatment of prostate cancer.
  • Fewer side effects compared to other microtubule disruptors.

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Lecture 4 - Topoisomerase Inhibitors and Microtubule Inhibitors PDF

Description

Explore DNA topoisomerases and their crucial role in DNA replication and transcription. Learn about different types of topoisomerases and inhibitors like camptothecin and anthracyclines. Understand how these inhibitors disrupt DNA processes, leading to apoptosis.

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