Pharmacology Exam 6

  1. Alkylating agents
    • nitrogen mustards
    • ethylenimines
    • alkyl sulfonates
    • nitrosoureas
  2. Alkylating agent mechanism of action
    molecule has 2 alkyl chloride groups, each has the cl- removed and form an adduct on N7 of guanine causing the DNA to become cross linked
  3. Nitrogen mustards
    • cyclophosphamide
    • ifosfamide
  4. Cyclophosphamide
    • a prodrug that must be activated by P450
    • converted into aldophosphamide which is converted into acrolein and phosphoramide mustard
    • both are cytotoxic but phosphoramide mustard is the most active agent
  5. Nitrosoureas
    • carmustine
    • streptozocin
    • no activation by P450 required
    • crosses BBB
  6. Alkylating related agents
    • cisplatin
    • carboplatin
  7. Cisplatin
    platinum is the reactive molecule that forms an adduct with N7 of guanine which Cl is removed
  8. Carboplatin
    analog of cisplatin
  9. Alkylating agent major toxicity
    bone marrow depression with leukopenia and thrombocytopenia
  10. Cyclophosphamide/ifosfamide toxicity
    • hemorrhagic cystitis
    • reduced by co-administration of MESNA
  11. Cisplatin/Carboplatin toxicity
    • ototoxic
    • nephrotoxic
    • nephrotoxicity can be reduced by chloride diuresis and hydration
  12. Nitrogen mustards used for
    hematologic and solid tumors
  13. Thiotepa used for
    ovarian cancer
  14. busulfan used for
    chronic myeloid leukemia
  15. Nitrosoureas used for
    brain tumors
  16. Streptozocin used for
    insulin secreting islet cell carcinoma of the pancreas
  17. Antimetabolites
    • folic acid analogs
    • purine analogs
    • pyrimidine analogs
  18. Folic acid analogs
    • methotrexate
    • mimic structure of folic acid to disrupt folic acid biosynthesis pathway
  19. Methotrexate mechanism of action
    • DHFR is the primary site of action
    • prevents formation of tetrahydrofolic acid and accumulation of DHF polyglutamate (inhibitory)
    • Purine and thymidylate synthesis ceases, stoping DNA and RNA synthesis
  20. mechanisms of resistance to methotrexate
    • impaired transport into cell
    • impaired polyglutamate formation
    • increased or altered dihydrofolate reductase
    • decreased thymidylate synthase
  21. Most important mechanism of resistance to methotrexate
    • at DHFR
    • cell can have high levels of DHFR
    • cell can have altered DHFR that will not bind MTX
  22. One of the most commonly used chemotherapeutic agents
  23. Toxicities with methotrexate
    • bone marrow suppression
    • nephrotoxicity
  24. Bone marrow suppression with MTX can be avoided with use of
  25. Nephrotoxicity with MTX can be avoieded by use of
    sodium bicarbonate to alkalinize urine
  26. Purine antagonists
    • mercaptopurine
    • thiguanine
    • cladribine
    • fludarabine phosphate
  27. Purine antagonist mechanism of action
    • blocks multiple enzymes
    • purine compound that contains S which can bind to the enzyme and mymic natrual purines
    • inhibits purine biosynthesis
  28. Mercaptopurine/Thioguanine
    • prodrugs that must be activated
    • activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form
  29. Pyrimidine antagonists
    • fluorouracil
    • cytarabine
    • gemcitabine
    • capecitabine
  30. 5-flurouracil mechanism of action
    inhibits thymidylate synthetase
  31. Uses for 5-FU
    • metastatic carcinomas of breast and GI tract
    • hepatoma
    • carcinomas of ovary, cervix, bladder, prostate, pancreas and oropharyngeal areas
  32. MTX resistance can be acquired in several ways. Which is the most obvious, specific and direct?

    B. increased or altered dhfr
  33. Plant alkaloids
    • natural compounds
    • higher bioavailability
    • steady state metabolism
    • much safter than other compounds
    • not as potent as synthetic compounds, but much less toxicity
  34. Plant alkaloid classes
    • vinca alkaloids
    • podophyllotoxins
    • camptothecins
    • taxanes
  35. Vinca Alkaloids
    • vinblastine
    • vincristine
  36. Vinca alkaloid mechanism of action
    • bind to microtule protine tubulin
    • terminates assembly of microtubles
    • results in mitotic arrest at metaphase
  37. Vinblastine toxicity
    • n/v
    • marrow depression
    • alopecia
  38. Therapeutic uses of vinblastine
    • systemic hodgkin's disease
    • lymphomas
  39. Taxanes
    • paclitaxel
    • docetaxel
    • derived from Yew Tree
  40. Taxane mechanism of action
    enhancement of tubulin polymerization causing unstoppable microtubule growth during m phase
  41. One of the biggest molecules that can be metabolized by CYP2C8
  42. Toxicity with paclitaxel
    • neutropenia
    • thrombocytopenia
    • peripheral neuropathy
  43. Toxicity with Doxetaxel
    • bone marrow suppression
    • neurotoxicity
    • fluid retention
  44. Uses of paclitaxel
    ovarian and advanced breast cancer
  45. Uses of docetaxel
    advanced breast cancer
  46. Antibiotics
    • Anthracyclines
    • Dactinomycin
    • plicamycin
    • mitomycin
    • bleomycin
  47. Anthracyclines
    • doxorubicin
    • daunorubicin
    • similar to napthalene
  48. Anthracycline mechanisms of action
    • High affinity for binding DNA through intercalation
    • DNA strand scission via topoisomerase II
    • Bind membranes altering fluidity
    • Generation of semiquinine free radicle and oxygen radicls which can cleave DNA
  49. Anthracylcine toxicity
    • bone marrow depression
    • total alopecia
    • cardiac toxicity
  50. Therapeutic use of doxorubicin
    • carcinomas of breast, endometrium, ovary, testicle, thyroid & lung.
    • Eqing's sarcoma and osteosarcoma
    • cannot be used with liver problems, will cause toxicity
  51. Daunorubicin uses
    acute leukemia
  52. Hormonal agents
    • estrogen and androgen inhibitors
    • gonadotropin releasing hormone agonists
    • aromatase inhibitors
  53. Anti-estrogens
    • tamoxifen
    • raloxifene
    • faslodex
  54. Tamoxifen
    • prodrug that must be activated by CYP2D6
    • efficacy could be effected by polymorphisms
  55. Tamoxifen mechanism of action
    • selective estrogen receptor modulator
    • antagonist in breast tissue
    • agonist in endometrium
    • causes the re-expression of a tumor suppressor gene known as maspin, which is repressed in breast cancerous cells.
  56. Tamoxifen toxicity
    • hot flashes
    • fluid retention
    • nausea
  57. Tamoxifen therapeutic use
    • metastatic breast cancer
    • patients with estrogen-receptor positive tumors
    • potential as preventative therapy in women with breast cancer risk
  58. Aromatase inhibitors
    • aminogluthethimide
    • anastrazole
  59. Aminogluthethimide mechanism of action
    • low dose aromatase inhibitor
    • high dose P450 inhibitor
  60. Aminogluthethimide toxicity
    • dizziness
    • lethargy
    • visual blurring
    • rash
  61. Therapeutic use of aminogluthethimide
    ER and PR positive metastatic breast cancer
  62. Misc. Anticancer agents
    • asparaginase
    • hydroxyurea
    • mitoxantrone
    • mitotane
    • retinoic acid derivatives
    • amifostine
  63. Asparaginase mechanism of action
    • breaks down aparagine to aspartic acid in cancer cells
    • asparagine is required for DNA synthesis and cell survival
    • neoplastic cells require external sources of asparagine because the levels of aspargine synthetase is reduced
  64. Uses of asparaginase
    treats childhood acute leukemia
  65. Toxicity of asparaginase
    can cause anaphylactic shock
  66. Biological modifiers
    • interferon
    • interleukin
  67. Interferon and interleukin mechanism of action
    • synthesized against foreign molecules/infection
    • interfere with cancer cells and stop growth
    • encourage killer T cells to attack cancer cells
    • encourage cancer cells to send out chemicals that attract the immune system
  68. Interferon and interleukin uses
    • kidney cancer
    • malignant melanoma
    • multiple myeloma
    • some leukemia types
  69. Interferon and interleukin toxicity
    • fatigue
    • flu like symptoms
    • diarrhea
    • loss of appetite
    • bone marrow effects
    • increased infection risk
  70. Monoclonal antibody based cancer treatment
    • monoclonal antibodies specifically bind target cells which stimulate immune system to attack tumor cells
    • synthesized from B cells not T cells
Card Set
Pharmacology Exam 6
Antineoplastics 2