Cancer Chemotherapy #1 - Chapter 54

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Cancer Chemotherapy #1 - Chapter 54
2013-03-03 22:26:09
Cancer Chemotherapy Pharmacology

Cancer Chemotherapy - Chapter 54 - Part #1
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  1. Cell cycle-nonspecific drugs (CCNS)
    An anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in the resting phase
  2. Cell cycle-specific drugs (CCS)
    An anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G-0 or resting phase
  3. Growth fraction
    The proportion of cells in a tumor population that are actively dividing
  4. Log-kill hypothesis
    • A concept used in cancer chemotherapy to
    • mean that anticancer drugs kill a fixed proportion of a tumor cell population, not a fixed number of tumor cells.

    • For example, a 1-log-kill will decrease a tumor cell population by one order of
    • magnitude

    •i.e. 90% of the cells will be eradicated
  5. Myelosuppressant
    • A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.
    • Myelosuppression is a side effect of some cancer treatments. When myelosuppression is severe, it is called myeloablation.
  6. Oncogene
    Oncogenes are genes that are responsible for the conversion of normal cells into cancer cells.
  7. Rescue therapy
    The administration of endogenous metabolites to counteract the effects of anti-cancer drugs on normal cells.  A strategy for ameliorating the toxic effects of anticancer drugs. 

    • For example, high doses of methotrexate are given for 36-48 hours,
    • –Leucovorin (tetrahydrofolate) which is accumulated preferentially by normal cells is then administered,
    • –This results in the rescue of normal cells since leucovorin bypasses the dihydrofolate reductase step of folate synthesis.
  8. What is a Vesicant?
    A blister agent, or vesicant, is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severe chemical burns, resulting in painful water blisters on the bodies of those affected

    Vesicants cause blistering and other tissue injury that may be severe and can lead to tissue necrosis (tissue death).
  9. What does the word Neoplasia mean?
    New growth
  10. Another term for neoplasm?
  11. ___________ tumors are characterized by local invasion and distant metastasis.
    Malignant tumors
  12. What are the characteristics of cell neoplasia?
    • Cells that have undergone malignant
    • transformation express signs of immaturity such as the expression of fetal antigens.

    They may show chromosomal abnormalities

    They may have altered metabolic pathways
  13. 3 reasons for the "genesis" of cancer cells?
    • 1   one or more mutations in its DNA which can be inherited or acquired
    • 2  Activation of proto-oncogenes to oncogenes
    • 3  Inactivation of tumor suppressor genes
  14. What is Dedifferentiation?
    • The multiplication of normal cells involves division of the stem cells in a particular tissue to give rise to daughter cells. 
    • These daughter cells differentiate to become mature cells.
    • Cancer cells show a reverse process
  15. What are the characteristics of cancer cells?
    •  Dedifferentiation

    •  Uncontrolled proliferation

    •  Invasiveness

    •  The ability to metastasize

    •  Cancer cells and normal cells are so similar in many respects that it is difficult to find areas of selective toxicity
  16. Metastases
    Metastases are secondary tumors that are released from the primary tumor
  17. What is the principle cause of of morbidity and mortality in cancer?
  18. A __________ is any physical, chemical, or biological factor that causes or promotes cancer. 
  19. Name 3 things considered to be carcinogenic.
    • Chemicals,
    • radiation,
    • viruses
  20. _______________ genes are genes that
    inhibit the transformation of normal cells into malignant cells.
    Tumor suppressor
  21. Damage to the _________________ gene is associated with cancers of the breast, lung, brain, colon, and bone.
    p53 tumor suppressor
  22. Cancer chemotherapy is based on the principle of __________________. 
    selective toxicity

    CCNS drug OR CCS drug?
    They form reactive molecular species that alkylate nucleophillic groups on DNA bases, particularly the N-7 position of guanine.

    –This  leads to cross-linking of bases, abnormal base pairing, and strand breakage. 





  26. How does tumor resistance to Alkylating Agents occur?
    Tumor resistance to these drugs occurs through:

    •  - increased DNA repair,
    •  - decreased drug permeability,
    •  - or the production of trapping agents such as thiols.
  27. Thiols contain a _____________  and are very nucleophillic.
    sulfur-hydrogen bond
  28. Cyclophosphamide - Clinical uses
    • Non-Hodgkin’s lymphoma,
    • breast and ovarian cancer,
    • and neuroblastoma
  29. Cyclophosphamide – pharmacokinetics
    Hepatic transformation is needed for antitumor activity.
  30. Cyclophosphamide - Toxicity
    • GI distress,
    • myelosuppression,
    • alopecia,
    • hemorrhagic cystitis,
    • cardiac dysfunction,
    • lung toxicity,
    • and SIADH
  31. What is SIADH?
    Syndrome of Inappropriate Antidiuretic Hormone secretion is characterized by excessive release of antidiuretic hormone from the posterior pituitary gland or another source.
  32. What are the symptoms of SIADH??
    hyponatremia as a result of an excess of water rather than a deficiency of sodium.
  33. Carmustine (BCNU)– pharmacokinetics
    • High lipophilicity that facilitates CNS entry,
    • used intravenously
  34. Carmustine (BCNU) – Clinical use
    • Hodgkin’s disease,
    • melanoma,
    • multiple myeloma,
    • brain cancer,
    • mycosis fungoides
  35. Carmustine (BCNU) –Toxicity
    • GI distress,
    • myelosuppression,
    • CNS dysfunction
  36. Name 3 Nonclassic Alkylating Agents?
    • Procarbazine,
    • Dacarbazine,
    • Bendamustine
  37. Procarbazine -Clinical use
    • Hodgkin’s and non-Hodgkin’slymphoma,
    • brain tumors
  38. Procarbazine - MOA
    Forms a metabolic that is an MAO inhibitor
  39. Procarbazine - Side effects / Risks
    Higher risk of secondary cancer (acute leukemia) than with other alkylating agents.
  40. Dacarbazine - clinical use
    • malignant melanoma,
    • Hodgkin’s lymphoma,
    • sarcomas,
    • and neuroblastoma
  41. Dacarbazine - Dose limiting toxicity?
  42. Dacarbazine - Adverse effect
    It is a potent vesicant
  43. Bendamustine- clinical use
    • CLL,
    • Hodgkin’s and non-Hodgkin’s lymphoma,
    • multiple myeloma,
    • and breast cancer
  44. Bendamustine - side effects
    Has only partial cross resistance with other alkylating agents.
  45. Name the 3 Platinum Analogs.
    • Cisplatin (Platinol),
    • Carboplatin,
    • Oxaliplatin
  46. Another name for Cisplatin?
  47. Cisplatin - Clinical uses
    • Testicular,
    • bladder,
    • ovary,
    • uterine,
    • head and neck cancers
  48. Cisplatin – Toxicity
    • GI distress,
    • myelosuppression,
    • neurotoxicity,
    • (peripheral neuropathy and acoustic nerve),
    • renal damage
  49. Cisplatin – Pharmacokinetics
    • Used intravenously,
    • widely distributed and cleared,
    • unchanged by the kidneys
  50. Carboplatin
    Second generation platinum analog

    •Less renal and GI toxicity than Cisplatin

    • •Does not require pretreatment hydration
    • and is therefore less cumbersome to administer
  51. Oxaliplatin
    Third generation platinum analog

    •No cross resistance with Cisplatin and Carboplatin
  52. Oxaliplatin - Clinical use
    •Useful for colorectal cancer
  53. Oxaliplatin - Toxicity
    Neurotoxicity is the primary dose-limiting toxicity.
  54. The Antimetabolites are structurally similar to __________________.
    endogenous compounds
  55. ANTIMETABOLITES - Antagonist of what?
    Antagonists of

    •  - folic acid(methotrexate),
    •  - purines (mercaptopurine),
    •   - or pyrimidines (fluorouracil).
    They are CCS drugs acting primarily in
    which phase of cell growth?
    the S phase
  57. ANTIMETABOLITES - How do they react with the immune system?
    They have immunosuppressant actions
  58. Name four ANTIMETABOLITES.
    One of them is a prodrug
    • Methotrexate
    • Mercaptopurine (6-MP)
    • Fluorouracil (5-FU)
    • Capecitabine (prodrug of 5-FU)
  59. Methotrexate – Pharmacokinetics
    • Both oral and IV administration afford good tissue distribution except to the CNS.
    • Excreted unchanged by the kidneys.
    • Adequate hydration is required to prevent crystallization in renal tubules
  60. Methotrexate - MOA
    • •Substrate for and inhibitor of dihydrofolate reductase.
    • •This interferes with nucleic acid and protein synthesis.

    • Tumor cell resistance mechanisms include decreased drug accumulation, changes in dihydrofolate reductase, increased formation of dihydrofolate reductase, and
    • decreased formation of cytotoxic metabolites of methotrexate
  61. Methotrexate - –Clinical use
    • Acute lymphoblastic leukemia,
    • choriocarcinoma,
    • head and neck cancer,
    • testicular cancer,
    • osteogenic sarcoma,
    • rheumatoid arthritis,
    • psoriasis,
    • and it is also used as an abortifacient
  62. Mercaptopurine (6-MP) - MOA
    Purine antimetabolite which is activated by hypoxanthine-guanine phospho-ribosyltranferase (HGPRTase) to toxic nucleotides that inhibit several enzymes involved in purine metabolism.

    A Prodrug
  63. Mercaptopurine (6-MP) - Resistance
    • decreased activity of HGPRTase,
    • or increased inactivation of the toxic nucleotide
  64. Mercaptopurine (6-MP) – Pharmacokinetics
    Low oral bioavailability due to first pass metabolism. 

    The metabolism of mercaptopurine is inhibited by allopurinol.
  65. Mercaptopurine (6-MP) - Clinical use
    Childhood acute leukemia
  66. Mercaptopurine (6-MP) – Toxicity
    • Bone marrow suppression,
    • and hepatic dysfunction
  67. Fluorouracil (5-FU) - MOA
    Transformed to 5-FdUMP which inhibits thymidylate synthase and leads to “thymineless” death of cells.
  68. Fluorouracil (5-FU) – Resistance
    • Decreased activation of 5-FU,
    • increased thymidylate synthase activity,
    • and reduced drug sensitivity of this enzyme
  69. Fluorouracil (5-FU) – Pharmacokinetics
    • Given IV,
    • widely distributed including the CSF,
    • Elimination is by metabolism.
  70. Fluorouracil (5-FU) - Clinical use
    • Breast,
    • colon,
    • rectum,
    • stomach,
    • and pancreas,
    • topically used for skin cancer
  71. Fluorouracil (5-FU) – Toxicity
    • GI distress,
    • myelosuppression,
    • and alopecia
  72. Capecitabine– Pharmacokinetics
    • A prodrug which is ultimately converted to 5-FU inside the cell.
    • Given orally
    • Less toxic than IV 5-FU
  73. Capecitabine - Clinical use
    Widely used in the treatment of metastatic breast cancer.
  74. Capecitabine - Toxicity
    • diarrhea,
    • hand-foot syndrome
  75. What is hand-foot syndrome?
    hand-foot syndrome – swelling, redness, and pain  of hands and feet