DDT 9

• Fundamental techniques of cancer therapy

  1. surgery
  2. radiation therapy
  3. chemotherapy
• mechanisms of chemotherapy

  • topoisomerase inhibitors
  • alkylating agents
  • antimetabolites
  • monoclonal antibodies
• intercalating agents

  • planar aromatic / hetero-aromatic ring system , can easily insert into DNA double helix
• doxorubicin is an intercalating agent

  • very effective , broad spectrum of solid tumours
  • acts as topoisomerase 2 poison by stabilizing the complex formed between DNA and topoisomerase 2
• numerous stabilized DNA-enzyme complexes trigger apoptosis
• Doxorubicin binds to GC base pairs causing a buckle in the DNA

  • preventing van der waals contacts
  • distort structure
  • stabilized by hydrogen bonding and pi-pi interactions
• Dactinomycin is an intercalating anti-cancer agent
• structure of dactinomycin

  • 3 fused aromatic rings
  • 2 indentical pentapeptide side chains
  • used for peadiatric solid tumours
• dactinomycin intercalates between GC bases

  • likes to go between two G bases beside each other on opposite strands.
• dactinomycin bound to DNA.

  • held by aromatic pi-pi interactions between tricyclic ring and DNA bases
  • stabilized by hydrogen bonding to nucleic acid bases
  • interferes with topoisomerase 2
  • stops replication and transcription
• mitotic spindles are microtubule structures that form during cell division
• anti-cancer drugs also act on tubulin
• tubulin is a protein needed for cell division

  • its a building block for microtubules which get polymerised/depolymerised in cell division
• anti-cancer drugs can bind to tubulin to prevent polymerization or bind to microtubules and prevent depolyemerization
• Vinticristin and paclitaxel are both anti cancer drugs that act on tubulin.
• Vinticristin binds to tubulin and prevents assembly of microtubules.

  Stops mitosis in metaphase
• paclitaxel stabilizes microtubules which stops the normal breakdown of microtubules in cell division.

  Blocks cell divsion and triggers apoptosis
• Alkylating anti-cancer agents have :

  • highly electrophilic groups
  • form covalent bonds with nucleophilic groups
  • prevents replication and transcription
• Alkylating anticancer agents can cause :

  • intra and intertstrand crosslinking
  • alkylation of nucleic acid base cause miscoding.
  • toxic side effects as its non-selective
• Intrastrand crosslinking occurs on the same strand.
• interstrand crosslinking occurs between 2 strands
• Nitrogen mustards are alkylating agents that contain an N atom attached to two R groups (alkyl). They react with DNA bases, causing crosslinks and preventing replication and transcription.
• Cisplatin is a platinum compound that forms intrastrand crosslinks by binding to guanines on opposite strands of DNA, leading to DNA damage and cell death.
• Chlormethine is an alkylating agent and is an example of a nitrogen mustard.
• Chlormethine causes interstrand and intrastrand cross linking and prevents cell replication.
• Chloromethine has to chlorine leaving groups.
• Chlormethine has an intramolecular Sn2 mechanism of action.
• DNA repair mechanisms include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination repair (HR), nonhomologous end joining (NHEJ), and apoptosis.
• The NER pathway repairs bulky lesions caused by UV radiation or chemical agents such as cisplatin.
• The BER pathway removes small modifications from bases, including oxidation products and deamination products.
• Melphalan works by inhibiting protein synthesis through DNA damage caused by its alkylating properties.
• Melphalan is used as chemotherapy for multiple myeloma and other cancers.