Cancer Therapies: Cytotoxic, Targeted, and Immunotherapy
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Questions and Answers

A patient is prescribed 6-Mercaptopurine. To prevent the buildup of inactive metabolites, which drug could be co-administered, and what effect would this combination have on the 6-Mercaptopurine dosage?

  • Leucovorin; decrease the 6-Mercaptopurine dosage.
  • Allopurinol; increase the 6-Mercaptopurine dosage.
  • Leucovorin; increase the 6-Mercaptopurine dosage.
  • Allopurinol; decrease the 6-Mercaptopurine dosage. (correct)

Which of the following is the primary mechanism of action for thioguanine?

  • Incorporation into both DNA and RNA (correct)
  • Inhibition of dihydrofolate reductase (DHFR)
  • Inhibition of adenosine deaminase
  • Inhibition of ribonucleotide reductase

What structural modification in halogenated adenosine analogs contributes to their resistance to degradation by adenosine deaminase?

  • Halogenation at the C2 position (correct)
  • Acetylation at the N6 position
  • Methylation at the C6 position
  • Glycosylation at the N9 position

Pentostatin increases the efficacy of purine and pyrimidine analogs by blocking metabolism via inhibiting which enzyme?

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

Which of the following is used as rescue medication alongside methotrexate to prevent toxicity?

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

What is the mechanism of action of Tretinoin (ATRA) in the treatment of acute promyelocytic leukemia (APL)?

<p>Forcing differentiation of APL cells. (A)</p> Signup and view all the answers

Arsenic trioxide is used as a second-line treatment for APL because it induces what cellular process in cancer cells?

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

Pegaspargase is a pegylated form of asparaginase used in the treatment of ALL. What is a major side effect associated with its use?

<p>Allergic or hypersensitivity reaction (A)</p> Signup and view all the answers

Which of the following statements accurately describes the mechanism of action of Busulfan?

<p>It cross-links DNA by utilizing CH2 groups adjacent to sulfonate esters to attack the N7 position of guanine. (A)</p> Signup and view all the answers

How does Temozolomide exert its cytotoxic effect?

<p>By non-enzymatically generating a methyl carbocation that methylates N6 and N7 of guanine. (A)</p> Signup and view all the answers

Why should organoplatinum agents not be administered through aluminum-containing needles?

<p>Organoplatinum agents react with aluminum. (C)</p> Signup and view all the answers

Which of the following statements is correct regarding the general mechanism of action of organoplatinum agents?

<p>They cross-link DNA and interfere with DNA synthesis and cell replication. (D)</p> Signup and view all the answers

A patient is prescribed dacarbazine. What metabolic process is crucial for its activation, and what is the resulting reactive species?

<p>Oxidation via P450 enzymes, generating a methyl carbocation that methylates O6 and N7 of guanine. (D)</p> Signup and view all the answers

Why might Oxaliplatin be chosen over Cisplatin in treating certain cancers?

<p>Oxaliplatin has a different spectrum of activity, retaining effectiveness in patients who no longer respond to Cisplatin. (D)</p> Signup and view all the answers

A patient undergoing cisplatin treatment develops peripheral sensory neuropathy and hearing loss. What accounts for these toxicities?

<p>Toxicities of platinum similar to symptoms of heavy metal poisoning. (A)</p> Signup and view all the answers

A patient is starting procarbazine treatment. What crucial instruction regarding diet and medication should the patient receive?

<p>Limit tyramine intake to prevent MAO inhibition. (A)</p> Signup and view all the answers

Cyclophosphamide is administered as a prodrug. Which of the following strategies is essential for managing the toxicity associated with its metabolism?

<p>Using Mesna to detoxify acrolein, a toxic metabolite, preventing hemorrhagic cystitis. (D)</p> Signup and view all the answers

A researcher is investigating a new nitrogen mustard analog for cancer treatment. What modification would likely enhance the oral bioavailability of the compound?

<p>Modifying the aliphatic substituents to affect its absorption and distribution properties. (D)</p> Signup and view all the answers

Which of the following mechanisms is NOT a primary mode of action for anti-cancer antibiotics?

<p>Alkylation of DNA bases, leading to direct DNA damage and replication errors. (D)</p> Signup and view all the answers

A cancer research team is evaluating several anti-cancer antibiotics. Which agent relies solely on the generation of free radicals to induce DNA damage, without directly inhibiting topoisomerase II or alkylating DNA?

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

Why are anti-microtubule agents like taxanes and vinca alkaloids considered M-phase specific in their cytotoxic effects?

<p>They disrupt the formation or stability of the mitotic spindle, essential for cell division during mitosis. (D)</p> Signup and view all the answers

A patient's cancer treatment includes Irinotecan. By what mechanism does this drug exert its cytotoxic effect?

<p>Inhibition of topoisomerase I, stabilizing the cleavable complex and causing DNA damage during replication. (A)</p> Signup and view all the answers

A researcher aims to enhance the efficacy of 5-Fluorouracil (5-FU) in a cancer treatment regimen. Which cellular process does 5-FU directly disrupt to inhibit cancer cell proliferation?

<p>Blocking thymidylate synthase, leading to a decrease in thymidine nucleotides required for DNA synthesis. (C)</p> Signup and view all the answers

Methotrexate (MTX) is a widely used antimetabolite. How does MTX interfere with DNA synthesis to exert its cytotoxic effect on cancer cells?

<p>By inhibiting folate metabolism, which is essential for the synthesis of purines and thymidine. (D)</p> Signup and view all the answers

What is the primary mechanism of action of sodium thiosulfate when administered with cisplatin?

<p>Neutralizing active cisplatin in the kidneys to reduce nephrotoxicity. (A)</p> Signup and view all the answers

Which of the following is a common structural feature of anthracyclines and anthracenediones?

<p>A tetracyclic quinone-containing ring with an aminoglycoside side chain. (A)</p> Signup and view all the answers

What is the role of Topoisomerase II (Topo II) inhibition in the mechanism of action of anthracyclines?

<p>It generates reactive oxygen species (ROS) leading to DNA damage and breaks. (A)</p> Signup and view all the answers

Why does the metabolism at the C13 position of anthracyclines affect cardiotoxicity?

<p>The chemical group at C13 influences the formation of cytotoxic free radicals, with CH2OH being preferable over CH3 to reduce cardiotoxicity. (C)</p> Signup and view all the answers

How does Dactinomycin bind to DNA, and what effect does this binding have?

<p>It intercalates into DNA with cooperative binding, which leads to stronger, pseudoirreversible binding and inhibits Topo II. (A)</p> Signup and view all the answers

Mitomycin is a prodrug that cross-links DNA. Which functional groups are essential for its carcinostatic activity?

<p>Quinone, carbamate, and aziridine. (C)</p> Signup and view all the answers

How does Bleomycin differ from other anticancer antibiotics regarding its interaction with topoisomerase II?

<p>Bleomycin does not inhibit topoisomerase II; it primarily intercalates DNA. (A)</p> Signup and view all the answers

How do taxanes and epothilones affect microtubule dynamics, and what is the implication of this action?

<p>They enhance microtubule polymerization, inhibiting their function during the M phase of cell division. (D)</p> Signup and view all the answers

Which statement accurately compares the toxicological profiles of vincristine and vinblastine?

<p>Vincristine typically exhibits more CNS toxicity, while vinblastine is more prone to causing bone marrow suppression. (B)</p> Signup and view all the answers

Why is vedotin, a spindle toxin, typically administered as an antibody-drug conjugate (ADC) rather than as a standalone drug?

<p>Vedotin is too toxic to be used systemically on its own, and antibody conjugation helps target it specifically to cancer cells. (B)</p> Signup and view all the answers

How do camptothecins exert their cytotoxic effect on cancer cells?

<p>By inhibiting topoisomerase I, leading to single- and double-strand DNA breaks and preventing DNA religation. (B)</p> Signup and view all the answers

Why is Irinotecan administered as a prodrug?

<p>To allow for controlled release of the active drug within the tumor microenvironment after bioactivation. (B)</p> Signup and view all the answers

Epipodophyllotoxins require solubility enhancers for IV infusion due to their poor water solubility; what is a potential consequence of this formulation requirement?

<p>Hypersensitivity reactions to the solubility enhancers used in the formulation. (C)</p> Signup and view all the answers

How does fluorouracil (5-FU) disrupt pyrimidine synthesis and inhibit cell growth?

<p>By being converted into 5-F-dUMP, which irreversibly inhibits thymidylate synthase, an enzyme essential for DNA synthesis. (B)</p> Signup and view all the answers

Gemcitabine inhibits DNA synthesis through two mechanisms involving its di- and triphosphate forms. What are these mechanisms?

<p>The diphosphate inhibits ribonucleotide reductase, while the triphosphate gets incorporated into DNA, halting further synthesis. (A)</p> Signup and view all the answers

Capecitabine requires a critical enzyme for bioactivation. What is the significance of this enzyme in cancer therapy?

<p>It is a tumor-specific enzyme, leading to selective activation of capecitabine in cancer cells. (D)</p> Signup and view all the answers

In which stage of carcinogenesis does clinical evidence of the disease typically become apparent?

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

Which of the following is a key difference between traditional cytotoxic chemotherapy and targeted therapy?

<p>Cytotoxic chemotherapies directly interfere with cellular replication; targeted therapies recognize biomarkers on cancer cells. (D)</p> Signup and view all the answers

A patient undergoing traditional cytotoxic chemotherapy develops severe mucositis. What is the most likely reason for this side effect?

<p>Cytotoxic agents affect all rapidly dividing cells, including those in the GI tract. (B)</p> Signup and view all the answers

Which phase of the cell cycle involves the replication of the DNA genome?

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

During which phase of the cell cycle are cellular components such as enzymes and proteins needed for DNA synthesis produced?

<p>G1 phase (B)</p> Signup and view all the answers

Which of the following mechanisms of action is characteristic of cell cycle non-specific cytotoxic agents?

<p>Damaging DNA in any phase of the cell cycle (D)</p> Signup and view all the answers

Cancer immunotherapy, specifically checkpoint inhibitors, work by which of the following mechanisms?

<p>Boosting the immune system's ability to recognize and attack cancer (C)</p> Signup and view all the answers

What is the primary rationale behind the development of targeted therapies in cancer treatment?

<p>To selectively affect cancer cells with biomarkers essential for growth (A)</p> Signup and view all the answers

Flashcards

Carcinogenesis

The process of development of cancer, typically in three stages.

Stages of Carcinogenesis

Includes initiation, promotion, and progression leading to clinical disease.

Traditional Cytotoxic Therapy

Drugs that kill cancer cells by disrupting cell replication, with specific and non-specific actions.

Cell Cycle Specific Agents

Drugs that kill cells during specific phases of the cell cycle, like antimetabolites.

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Cell Cycle Non-Specific Agents

Drugs like alkylating agents that kill cells in any phase of the cell cycle.

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Targeted Therapy

Treatment designed to attack specific biomarkers on cancer cells with fewer side effects.

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Cancer Immunotherapy

Uses the immune system to recognize and combat cancer, featuring checkpoint inhibitors and CAR T-cell therapies.

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Phases of the Cell Cycle

Includes G1, S, G2, and M phases, essential for cell growth and division.

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Vinca Alkaloids

Inhibit microtubule function during M phase, causing cell division disruption.

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Vincristine

A Vinca alkaloid with more CNS toxicity; fatal if given intrathecally.

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Vinblastine

A Vinca alkaloid causing more bone marrow suppression than Vincristine.

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Camptothecins

Inhibit Topo-I, causing DNA strand breaks; active during the S phase.

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Topotecan

An important Camptothecin; given IV, metabolized by CYP3A4.

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Pyrimidine Antagonists

Inhibit pyrimidine synthesis during the S phase, halting cell growth.

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Fluorouracil

A pyrimidine antagonist; irreversibly inhibits thymidylate synthase.

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Gemcitabine

A cytidine analog that inhibits DNA synthesis; given IV.

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DNA Alkylating Agents

Chemicals that alkylate DNA, causing damage and dysfunction.

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Cyclophosphamide

A prodrug that converts to active metabolites to alkylate DNA.

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Mechanism of Action

Alkylation of DNA, leading to cross-linking and inhibition of transcription.

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Purine & Pyrimidine Antagonists

Class of drugs that inhibit DNA synthesis by blocking purine or pyrimidine metabolism.

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5-Fluorouracil (5-FU)

Inhibits thymidylate synthase, thus blocking DNA synthesis.

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Topoisomerase Inhibitors

Drugs that inhibit enzymes stabilizing DNA structure during replication.

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Anti-Cancer Antibiotics

Drugs that intercalate into DNA and generate radicals, causing damage.

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M-Phase Specificity

Characteristic of drugs that target the mitotic phase of cell division.

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Cytidine analogs

Compounds like azacitidine and decitabine that inhibit DNA methylation.

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6-Mercaptopurine

Prodrug that inhibits purine biosynthesis, converting via xanthine oxidase.

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Thioguanine

Prodrug incorporated into DNA/RNA, major action in purine metabolism.

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Methotrexate

Inhibits DHFR, blocking folic acid cycle, affecting purine and pyrimidine synthesis.

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Tretinoin

First-line treatment for APL, induces differentiation of cancer cells.

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Arsenic trioxide

Second-line treatment for APL, induces apoptosis in cancer cells.

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Asparaginase

Catalyzes conversion of L-asparagine, depriving leukemic cells.

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Pegaspargase

Pegylated form of asparaginase used for ALL with hypersensitivity reactions.

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Sodium thiosulfate

A compound that inactivates Cisplatin to protect kidneys.

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Anthracyclines

Tetracyclic compounds that intercalate DNA and inhibit Topo II, causing DNA damage.

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Dactinomycin

A drug that intercalates DNA with cooperative binding, leading to strong interactions.

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Mitomycin

A prodrug that causes DNA cross-linking via carcinostatic functional groups.

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Bleomycin

An anticancer drug that intercalates DNA but does not inhibit Topo II.

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Taxanes

Drugs enhancing microtubule polymerization and inhibiting it's function in M phase.

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Epothilones

Similar action to Taxanes but with different structure and better water solubility.

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Carmustine

A highly lipophilic chemotherapy drug administered intravenously in 10% ethanol.

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Lomustine

An oral chemotherapy agent used to treat specific cancers.

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Streptozocin

A natural product with water solubility, targeting islet cells in the pancreas.

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Procarbazine

An oral chemotherapy drug that generates methyl radicals to alkylate guanine.

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Dacarbazine

An intravenous drug requiring P450 enzyme activation to methylate guanine.

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Busulfan MOA

Mechanism involves CH2 groups attacking N7 of guanine, leading to cross-linking in DNA.

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Organoplatinum agents

Chemotherapeutics that cross-link DNA, affecting replication and causing heavy metal-like toxicities.

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Cisplatin

A nephrotoxic chemotherapy drug that is a hydroxylated active form of an organoplatinum compound.

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Study Notes

Carcinogenesis Stages

  • Carcinogenesis has three stages
  • Clinical disease usually appears in early stages of progression

Anti-Cancer Drug Classes

  • Traditional cytotoxic cancer therapy: Interferes with cell replication
    • Cell cycle specific agents (antimetabolites, microtubule inhibitors) act on specific cell cycle phases
    • Cell cycle non-specific agents (alkylating agents, antibiotics) target cells in any phase
    • Effective on rapidly dividing cells
      • Side effects: diarrhea, mucositis, myelosuppression
  • Targeted therapy: Recognizes biomarkers on cancer cells
    • Monoclonal antibodies and kinase inhibitors
    • Side effects profiles differ from traditional cytotoxic agents
  • Cancer immunotherapy: Boosts the immune system's ability to target cancer cells
    • Checkpoint inhibitors (PD-1/PD-L1, CTLA-4)
    • CAR T-cell therapy
    • Side effects are mainly immune-mediated

Cell Cycle Phases and Anti-Cancer Drugs

  • Cell cycle phases:
    • G1: Synthesis of cellular components for DNA synthesis
    • S: Replication of DNA
    • G2: Synthesis of cellular components for mitosis
    • M: Cell division into two identical daughter cells
  • Anti-cancer drug classification based on cell cycle activity:
    • Cell cycle specific drugs are effective against rapidly dividing cells like hematologic cancers
    • Cell cycle non-specific drugs are effective against both low/high-growth fraction cancers including solid tumors

DNA Alkylators

  • Structure: Extremely reactive electrophilic structures
  • Mechanism of action (MOA): Attack guanine bases (N7 or O6), forming covalent bonds and alkylating DNA
  • Examples: Nitrogen mustards, nitrosoureas, procarbazines, triazines, organoplatinum complexes
  • Alkylating agents kill cancer cells by cross-linking DNA and disrupting DNA replication and transcription
  • They are active in late G1 and S phase when DNA is exposed

Other Classes of Anti-Cancer Agents

  • Anticancer Antibiotics: Intercalate with DNA, inhibit Topo II, except bleomycin. Includes anthracyclines and anthracenediones (structure, MOA, side effects) and Dactinomycin (structure, MOA, side effects).
  • Mitosis Inhibitors (Taxanes): Enhance microtubule polymerization, inhibiting function during M phase. Examples: Paclitaxel, Docetaxel.
  • Topoisomerase Inhibitors (camptothecins): Inhibit DNA topoisomerase I, active during S phase, causes DNA single and double strand breaks. Includes Topotecan and Irinotecan.
  • Topoisomerase Inhibitors (epipodophyllotoxins): Inhibit DNA topoisomerase II, active in S and G2 phase, highly water insoluble. Includes Etoposide and Teniposide.
  • Antimetabolites: Interfere with folic acid or nucleotide synthesis, blocking purine and pyrimidine biosynthesis during S phase. Includes pyrimidine antagonists (e.g., Fluorouracil, Cytarabine) and purine antagonists (e.g., 6-Mercaptopurine).

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Description

This lesson covers the three main types of cancer therapies: cytotoxic, targeted, and immunotherapy. Cytotoxic therapies interfere with cell replication, targeted therapies recognize biomarkers, and immunotherapies boost the immune system. Each therapy class possesses distinct mechanisms and side effect profiles.

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