MS1, Block 2 Anti-cancer chemotherapy

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BigDee
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46449
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MS1, Block 2 Anti-cancer chemotherapy
Updated:
2010-11-01 17:24:59
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chemotherapy
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Ihnatt Chemotherapy
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  1. Features of cancer cells different from most normal cells (5)
    • •Constant DNA synthesis (Alkylating agents, anti-tumor antibiotics)
    • •High metabolic rate (Antimetabolites)
    • •Continuous cell division –mitosis (Microtubule-targeting agents)
    • •Fast growth – need new blood supply (Anti-angiogenic drugs)
    • •Some tumors depend on hormones
  2. Cell cycle specific chemotherapeutic agents that are S phase specific
    • Attack cell during DNA synthesis
    • E.g., antimetabolites (purines, pyrimidines)
  3. Cell cycle specific chemotherapeutic agents that are M phase specific
    • Attack cell at mitosis
    • E.g., taxol, vincas
    • (MTV)
  4. Use Body Surface Area (BSA) (sq root((weight * height)/3600)) due to?
    • Better correlation between THERAPEUTIC and TOXIC doses between patients and between species
    • Correlates well with cardiac output (Important with cardiotoxic drugs like the anthracyclines)
    • Affects HEPATIC AND RENAL ELIMINATION of drugs
  5. Chemotherapeutic agents are Typically cycled every month, why?
    Due to side-effects of drugs
  6. Criteria for combination chemotherapy:
    • Should be active alone against the tumor of interest
    • Should act by different mechanisms of action
    • Should have different dose-limiting toxicities (DLTs)
    • Should have different mechanisms of resistance
    • Should include cell cycle specific and non-specific agents
  7. added to methotrexate treatment to rescue normal cells; agents having different toxicities
    leucovorin
  8. Classification of Chemotherapeutic Agents:ALKYLATING AGENTS these work by what method?
    • Mechanism: Bind covalently to the DNA molecule
    • Attack ANY dividing cell
  9. ALKYLATING AGENTS stop cell growth by Inhibit DNA synthesis (S phase)
    Physically prevent DNA synthesis enzymes (polymerase) from passing adduct
  10. alkylating agents that Can be removed by the cell DNA repair enzymes
    Monoadducts: easier to fix than crosslinks
  11. Classification of drugs that work by;
    Mechanism: most act by ALKYLATION or INTERCALATION
    BOTH mechanisms → inhibition of DNA synthesis
    ANTITUMOR ANTIBIOTICS
  12. ANTITUMOR ANTIBIOTICS
    CLASSES:
    ANTHRACYCLINES: intercalators (2 of them)
    • epirubicin
    • Doxorubicin
    • bleomycin
  13. Bleomycin
    • Generates reactive oxygen species (Superoxide (O2-•) and hydroxy radical (OH•))
    • Results in DNA strand breaks (Similar to radiation, RANDOM breaks)
  14. Antimetabolites (
    • Block the biosynthesis or use of normal cellular metabolites (“materials for building DNA”)
    • Decrease DNA synthesis
    • MOA of inhibiting DNA synthesis:
    • ØRemove critical proteins in DNA replication
    • ØBeing “false substrates” for DNA synthetic enzymes
  15. class of antimetabolites that is a FOLIC ACID analogue
    methotrexate (also used to block immune cells for arthritis)
  16. class of antimetabolites that is a PYRIMIDINE analogues (3)
    • fluorouracil (5-FU) (false substrates)
    • gemcitabine
    • capecitabine
  17. class of antimetabolites that is a PURINE analogues
    6-mercaptopurine
  18. class of antimetabolites that are PLANT ALKALOIDS; VINCAS
    • vincristine
    • vinblastine
    • (Isolated from the periwinkle bush
    • Mechanism: arrest cell division by preventing the formation of the mitotic spindle)
    • cause diarhea
    • Block M phase
  19. class of antimetabolites that are PLANT ALKALOIDS; CAMPTOTHECINS
    and method of action
    • irinotecan
    • topotecan

    • MOA: inhibit topoisomerase I - an enzyme responsible for unwinding DNA during synthesis Inhibition of topo I causes DNA strand breaks
    • Block M phase
  20. class of antimetabolites that are PLANT ALKALOIDS; EPIPODOPHYLLOTOXINS
    and method of action
    • etoposide
    • teniposide

    • MOA: inhibit topoisomerase II → DNA strand breaks
    • enzyme responsible for unwinding DNA during synthesis
  21. class of antimetabolites that are PLANT ALKALOIDS; TAXENES
    and method of action
    • paclitaxel
    • docetaxel

    MOA: stabilize microtubules → block cell division
  22. Enzyme that removes a vital amino acid (asparagine) critical to the growth of some tumor cells
    • ASPARAGINASE
    • PEGASPARAGINASE
  23. Antihelmitic drug that non-specifically stimulates immune system
    Used as adjunct agent in colon cancer
    Levamisole
  24. biological response modifier
    PCOL: vaccine against bovine bacteria that non-specifically enhances the immune system to remove tumor cells
    Treats bladder cancer
    Bacillus Calmette-Guerin (BCG):
  25. MOST COMMON DOSE-LIMITING TOXICITY
    DOSE and AGENT related
    causes neutropenia
    MYELOSUPPRESSION (bone marrow suppression):
  26. decreased neutrophils
    Measured by the absolute neutrophil count (ANC)
    ↑ infection incidence
    TREATMENT: Growth factors (immunotherapy lecture)
    neutropenia
  27. Most common types of myelosuppression
    • ERYTHROPENIA (↓ RBCs)
    • THROMBOCYTOPENIA (↓ platelets)
    • TREATMENT:
    • Epoetin-α (immunotherapy lecture)
    • Blood tranfusions
    • ANEMIA
  28. ↓Hb secondary to RBC loss
    ANEMIA
  29. Time course of Myelosuppresion (why chemo is cycled)
    Many agents: onset of suppression at 7 days, nadir at 10-14 days , back to normal by 28 days
  30. Localized tissue damage if drug is administered outside a vein
    EXTRAVASATION NECROSIS
  31. TREATMENTS for extravasation necrosis for VINCAS and OTHER AGENTS
    • VINCAS: heat and hyaluronidase
    • OTHER AGENTS: neutralizing solution - sodium thiosulfate for mechlorethamine
  32. GI TOXICITIES of chemo
    • NAUSEA AND VOMITING (Probably the most UPSETTING to a patient)
    • COMMON WITH: cisplatin
  33. Treatment of GI TOXICITIES of chemo
    • 5HT3 antagonists (ondansetron, granisetron, etc.) - work in CNS to decrease emetogenic potential of agents - very effective
    • 5HT3 = Serotonin in CNS
  34. irritation of mucus membranes
    5-FU and methotrexate are most common
    Can lead to cachexia and infection
    STOMATITIS
  35. common with topotecan and irinotecan
    DIARRHEA
  36. Bleomycin - drug is inactivated by an enzyme (bleomycin hydrolase) - absent in lungs causes what toxicity
    Mitomycin and nitrogen mustards also cause this also
    pulmonary toxicity
  37. Platinum analogues, cisplatin - direct renal cell death
    Amifostine: sulfhydryl containing drug that detoxifies free radicals that can lead to renal cell death
    RENAL TOXICITY
  38. Type of toxicity causing Numbness, trouble walking, loss of reflexes
    Common with vincristine
    Neurotoxicity
  39. Type of Toxicity that is Common with the ANTHRACYCLINES
    Damage extent proportional to total cumulative dose
    MOA: ↑↑reactive oxygen species in the myocardium
    Requires Iron
    Dexrazoxane: Chelates iron - ↓↓↓ ROS decreasing this toxicity
    CARDIOVASCULAR TOXICITY
  40. Bladder toxicity associated with cyclophosphamide and ifosfamide
    Due to a breakdown product of the drug, acrolein
    MESNA: drug that binds to acrolein and inactivates it
    HEMORRHAGIC CYSTITIS

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