W4 Pharmaco cancer

• Intercalating agents


  Cell cycle dependent drug
• Types of intercalating agents

  • Originally natural from plant or fungi
  • It is chromophore (colorful)
  • Target actively dividing cell
• Function of topoisomerase


  1. Preventing DNA from getting tangled

  2. Relieving pressure in supercoiled DNA during DNA replication

  
• Topoisomerase I inhibitors


  • CAMPTOTHECINS
  • Topotecan
  • Irinotecan

  
• Topoisomerase II inhibitors


  • ANTHRACYCLINES
  • Doxorubicin
  • Idarubicin
  • Epirubicin
  • Mitoxantrone
  • EPIPODOPHYLLOTOXINS
  • Etoposide
  • Teniposide
  • OTHERS
  • Beomycin (DNA Strand Breaker)

  
• RNA polymerase Inhibitors


  • Actinomycin D
  • Plicamycin

  
• Camptothecins


  Derived from Camptotheca acuminate
• Etoposide


  Derived from podophyllotoxin
• Bleomycin


  DNA Strand Breaker

  
• Reanneal


  The process of reformation of a double-stranded DNA molecule from single strands produced by thermal dissociation

  
• Topoisomerase I inhibitors


  • Camptothecin, topotecan, irinotecan have the same mechanism of action

  
• Topotecan


  Not a prodrug, does not need to be activated
• Mechanism of action of irinotecan

  1. Irinotecan becomes SN-38

  2. SN-38 binds to topoisomerase I-DNA complex

  3. Impaired religation of DNA strands

  4. DNA damage and apoptosis

  
• Irinotecan has contrasting effects on dividing and non-dividing tissues

  
• Pharmacokinetics of topotecan


  1. Topotecan undergoes reversible pH-dependent hydrolysis of its lactone moiety

  2. Glucuronidation of both lactone and open-ring forms

  3. Dealkylation of inactive glucuronide conjugates

  
• Pharmacokinetics of irinotecan


  1. Irinotecan is slowly bioactivated in the liver

  2. SN-38 is glucuronidated before elimination

  3. CYP3A4 cleaves the terminal piperidine ring

  4. Excretion is renal

  
• Inactive metabolites of irinotecan can be converted back to active metabolite in the GI tract

  
• Mechanism of resistance to irinotecan

  Glucuronidation of SN-38 by UGT1A1

  
• Side effects of irinotecan

  • Early onset and late onset diarrhea
  • Patients with UGT1A1*28 polymorphism at higher risk of toxicities

  
• Anthracyclines


  Cytotoxic anticancer agents that work by damaging DNA and generating free radicals

  
• Mechanism of action of anthracyclines

  1. Intercalation in DNA

  2. Inhibition of transcription by inhibiting topoisomerase II

  3. Generation of free radicals

  
• Mitoxantrone


  Classified as an anthracenedione, lacks a sugar moiety, has reduced cardiovascular toxicity

  
• Mechanism of action of mitoxantrone


  1. Intercalates into DNA cleavage sites

  2. Inhibits human topoisomerase II

  
• Pharmacokinetics of anthracyclines


  • Need transporter to enter cell
  • ABCB1/MDR1 protein can pump doxorubicin out of cell

  
• Metabolism of anthracyclines


  1. Conversion to semiquinone

  2. Reduction to C13-alcohol

  3. Glycosidic cleavage to aglycone

  4. Conjugation of aglycone

  
• Mechanisms of resistance to anthracyclines

  • Drug efflux by P-glycoprotein
  • Decreased levels or mutations in topoisomerase II
  • Increased antioxidant defense

  
• Aglycone


  Cleavage of the glycosidic bond in the anthracycline molecule by cytosolic NADPH-dependent glucosidases leads to the formation of an anthracycline aglycone

  
• Anthracycline aglycone


  • It can undergo further conjugation with sulfate or glucuronic acid
  • This process increases the water solubility of the molecule, aiding in its excretion through urine
• Conjugation


  The anthracycline aglycone can undergo conjugation with sulfate or glucuronic acid
• Epipodophyllotoxins


  Topoisomerase 2 dependent

  
• Etoposide Mechanism of Action

  1. Topoisomerase II cleaves DNA

  2. Podophyllotoxin derivative binds

  3. Trapped enzyme-DNA complex

  4. DNA damage and apoptosis

  
• Teniposide has the same mechanism of action as etoposide
• Etoposide treatment triggers ROS generation and ERK activation in HK-2 cells. ROS promotes mitochondrial biogenesis and cytosolic ATP induction, which eventually enhance necrosis, but not apoptosis

  
• Bleomycin


  Derived from the bacterium Streptomyces verticillus, belongs to the glycopeptide family
• Bleomycin's Mechanism of Action


  1. Metal Ion Binding: Bleomycin requires a metal ion, usually iron (Fe²⁺), to function

  2. DNA Intercalation: The bleomycin-iron complex binds to DNA, partially inserting itself between the base pairs

  3. Reactive Oxygen Species (ROS) Generation: The bleomycin-iron complex can generate reactive oxygen species (ROS), particularly superoxide radicals

  4. DNA Scission: The generated ROS, especially hydroxyl radicals (OH•), can directly attack the sugar-phosphate backbone of DNA, causing single and double-strand breaks

  
• Unlike some DNA-damaging agents, bleomycin does not require cell division (mitosis) to be effective

  
• Mechanism of action of bleomycin

  1. Intercalation - Disrupts DNA structure and brings iron complex in close proximity

  2. Reactive Oxygen Species (ROS) Generation - ROS attack DNA backbone

  3. DNA Scission - ROS cause single and double-strand breaks in DNA

  
• Three types of topoisomerase II inhibitors

  1. Anthracyclines
• Topoisomerases are enzymes that regulate the winding/unwinding of DNA during transcription and replication.
• The anthracyclines are derived from Streptomyces peucetius var. caesius and include doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, and pirarubicin.