Drug Mech: Anticancer Drugs (Chemotherapy)

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Drug Mech: Anticancer Drugs (Chemotherapy)
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2011-03-01 19:28:22
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Drug Mech Anticancer Chemotherapy
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Drug Mech: Spring 2011, Anticancer Drugs (Chemotherapy)
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  1. What are the phases of the cell cycle?
    • Resting Phase:
    • G0 (GAP 0): no growth occurs

    • Interphase:
    • G1 (GAP 1): cell growth
    • S (DNA Synthesis): replication of DNA (duplication of each chromatid)
    • G2 (GAP 2): cell prepares to divide (each chromosome is composed of two chromatids in preparation for mitosis)

    • Mitotic Phase:
    • M (Mitosis): cell division (dividing chromatids between daughter cells via PPMAT = Prophase, Prometaphase, Metaphase, Telophase)




  2. What sequence of the cell cycle is common to eukaryotes (human cells)?
    G1 to S to G2 to M to cytokinesis
  3. What does the cell cycle of a typical malignant cell look like?
    All cells, normal and neoplastic (abnormal growth), must traverse a number of cell cycle phases before and during cell division. A schematic of the cell cycle of a typical malignant cell is shown below.

  4. What class of enzymes are involved in triggering events in the cell cycle?
    Kinases are involved in triggering events in the cell cycle.

    Kinases add phosphate to molecules (phosphorylate), and the modification can serve as a "switch" to turn events in the cell on or off.

    Cdk or cyclin dependent kinases regulate the cell cycle.
  5. What do proteases, transferases and nucleases do?
    • Protease enzyme: degrade proteins (for example, trypsin is a protease important in digestion)
    • Transferase enzyme: transfers molecules
    • Nuclease enzyme: degrade nucleic acids
  6. What is P53?
    p53 is a protein that functions to block the cell cycle if the DNA is damaged. If the damage is severe this protein can cause apoptosis (cell death).

    p53 levels are increased in damaged cells. This allows time to repair DNA by blocking the cell cycle.

    A p53 mutation is the most frequent mutation leading to cancer. An extreme case of this is Li Fraumeni syndrome, where a genetic a defect in p53 leads to a high frequency of cancer in affected individuals.
  7. The sputum (fluid coughed up from the lungs) of many smokers contain cells with mutations (errors) in the genes for p53. The smoking induced mutations appear to be an early signal showing that cancer of the lungs will follow. What is the likely relationship between early p53 mutation and the development of lung cancer?
    Mutations in p53 would prevent abnormal cells from dying by apoptosis.

    If the mechanism for eliminating abnormal cells is defective, then the cells will continue to divide and further damage their DNA. This process leads to cancer. Exposure to sun also causes apoptosis in damaged cells. This produces the familiar peeling and blistering associated with severe sunburn. Over many years, exposure to sun also leads to cancer. It is particularly interesting that smoke seems to cause a high frequency of p53 mutations.
  8. What are Cell Cycle Specific (CCS) anticancer drugs?
    Many of the effective anticancer drugs exert their action only on cells traversing the cell cycle (cycling cells); these drugs are known as cell cycle-specific (CCS) drugs. CCS drugs are not active against resting cells (i.e., cells that are in the G0 phase).
  9. What are Cell Cycle-Nonspecific (CCNS) anticancer drugs?
    Other anticancer drugs can sterilize tumor cells regardless of whether they are cycling or resting in the G0 phase; these particular drugs are known as cell cycle-nonspecific (CCNS) drugs. CCNS drugs can kill both G0 and cycling cells, although cycling cells are more sensitive.
  10. Which phase are cells most vulnerable to anticancer drugs?
    Cycling cells are more sensitive to anticancer drugs, or in other words, cells that are not in the G0 resting phase are more sensitive to anticancer drugs.
  11. What type of cancers are CCS drugs most effective in?
    In general, CCS drugs are most effective in hematologic cancers (affecting blood, bone marrow and lymph nodes) and solid tumors in which a large proportion of the cells are proliferating or are in the growth fraction.
  12. What type of cancers are CCNS drugs most effective in?
    CCNS drugs, many of which bind to and damage cellular DNA, are useful in low growth fraction solid tumors as well as in high growth fraction tumors.
  13. Which drugs are more effective against cancer: CCS or CCNS drugs?
    • Cell Cycle-Nonspecific (CCNS) are more effective than CCS because they can kill the cell regardless of what phase in the cell cycle the cell is in.
  14. What is a tumor stem cell vs. a non-stem cell?
    All effective CCS and CCNS drugs inactivate tumor stem cells, which are often only a small fraction of the cells in a tumor.

    Non-stem cells (i.e., tumor cells that have irreversibly differentiated) are considered sterile (harmless) by definition.
  15. How do CCS and CCNS drugs act against tumor stem cells?
    All effective CCS and CCNS drugs inactivate tumor stem cells, which are often only a small fraction of the cells in a tumor.

    Non-stem cells (i.e., tumor cells that have irreversibly differentiated) are considered sterile (harmless) by definition.
  16. Which drugs are Cell Cycle Specific (CCS)?
    • Antimetabolites
    • Bleomycin
    • Epipodophyllotoxins
    • Taxanes
    • Epothilones
    • Vinca Alkaloids
  17. Which drugs are Cell Cycle Nonspecific (CCNS)?
    • Alkylating Agents
    • Anthracyclines
    • Dactinomycin
    • Mitomycin
    • Camptothecins
  18. What is primary resistance?
    Primary resistance is the absence of response to cancer chemotherapy on the first exposure to currently available standard anticancer drugs.
  19. What is primary resistance attributed to?
    Primary resistance is a type of inherent resistance to drug therapy has been attributed to the genomic instability associated with the development of most cancers.

    In other words, primary resistance is due mainly to the instability of the cancer.
  20. What is acquired resistance?
    Acquired resistance develops in drug-sensitive tumors.

    It can be highly specific against a single drug due to alteration in the genetic apparatus (target modification) of the tumor with amplification or increased expression of one or more specific genes.

    Acquired resistance can also be a multidrug resistance (ie, resistance to a variety of anticancer drugs of differing structures).
  21. Which type of resistance is more common: primary resistance or acquired resistance?
    • Primary resistance is not common
    • Acquired resistance is very common
  22. How many drugs are involved in acquired resistance?
    It could be just one drug or it could be multidrug resistance. Acquired resistance develops in drug-sensitive tumors, but it could be resistance to a single or many drugs.
  23. Which type of resistance happens on the first exposure of a drug?
    Primary resistance
  24. What is Multidrug Resistance (MDR) attributed to?
    • Multidrug resistance (MDR) is often attributed to increased expression of a normal gene, the MDR1 gene, for a cell surface glycoprotein (P-glycoprotein) involved in drug efflux.
    • P-glycoprotein is a transport molecule that requires ATP to expel a variety of foreign molecules (not limited to anticancer drugs) from the cell.
  25. What is P-glycoprotein?
    Multidrug resistance (MDR) is often attributed to increased expression of a normal gene, the MDR1 gene, for a cell surface glycoprotein (P-glycoprotein) involved in drug efflux.

    P-glycoprotein is a transport molecule that requires ATP to expel a variety of foreign molecules (not limited to anticancer drugs) from the cell.
  26. What are other mechanisms involved in Multidrug resistance (MDR)?
    Other mechanisms of MDR involve overexpression of the multidrug resistance protein 1 (MRP1).

    MRP1 is a member of a superfamily of ATP-binding transmembrane transporters; it increases resistance to natural product anticancer drugs, such as vinca alkaloids, taxanes, and anthracyclines, by acting as a drug export pump.
  27. What two proteins are involved in Multidrug Resistance (MDR) by facilitating active drug efflux?
    • overexpression of MDR1 gene for cell surface P-glycoprotein
    • overexpression of protein 1 (MRP1)
  28. What two proteins pump anticancer drugs out of the cell via active efflux?
    • P-glycoprotein
    • MRP1 (protein 1)
  29. Which protein uses active efflux to export natural product anticancer drugs?
    protein 1 (MRP1)
  30. Can active efflux exhibited in Multidrug Resistance (MDR) be reversed?
    Yes. MDR can be reversed by administering drugs that inhibit efflux transporters such as calcium channel blockers (e.g., verapamil).
  31. Which class of drugs can inhibit efflux transporters?
    calcium channel blockers (e.g., verapamil)
  32. What are the three main toxicities related to the rate of cell growth?
    1) Bone Marrow Depression (Myelosuppression), due to damage to normal erythropoietic and leukopoietic cells.

    2) Nausea, Vomiting, Diarrhea (due to damage to the epithelial cells of the GIT).

    3) Alopecia (hair loss), due to damage to hair-follicle cells.
  33. What are similes for bone marrow depression?
    • bone marrow depression
    • myelosuppression
    • neutropenia
  34. What type of cells are damaged with myelosuppression?
    Bone marrow depression, also called myelosuppression, is due to damage of normal erythropoietic and leukopoietic cells.
  35. If this type of cell is damaged, it will cause nausea, vomiting and diarrhea.
    Nausea, Vomiting, Diarrhea may be due to damage to the epithelial cells of the GI Tract.
  36. What type of cell is damaged in alopecia?
    Alopecia, or hair loss, is due to damage of hair-follicle cells.
  37. Why do most anticancer drugs have the same general associated adverse effects?
    Most anticancer drugs have myelosuppression, nausea, vomiting, diarrhea and alopecia because the cells that are affected in anticancer drugs are the cells that replicate the most. The cells affected in these areas have a high turnover rate compared to most cells in the body.
  38. What are the five major anticancer drug classes?
    • Polyfunctional Alkylating Agents
    • Antimetabolites
    • Natural Products
    • Hormonal Agents
    • Protein Tyrosine Kinase Inhibitors
  39. Which drugs are included in the Polyfunctional Alkylating Agents?
    • 1) Bis(chloroethyl)amines
    • - Cyclophosphamide
    • - Mechlorethamine
    • - Chlorambucil
    • - Melphalan

    • 2) Nitrosoureas
    • - Carmustine (BCNU)
    • - Lomustine (CCNU)
    • - Semustine (Methyl-CCNU)

    • 3) Aziridines
    • - Thiotepa
    • - Triethylenemelamine

    • 4) Alkylsulfonates
    • - Busulfan

    • 5) Other Related Drugs
    • - Procarbazine
    • - Dacarbazine
    • - Altretamine
    • - Cisplatin, Carboplatin, & Oxaliplatin

  40. Which chemical structure were polyfunctional alkylating agents based on?
    Anticancer alkylating agents were developed based on the chemical structure and mechanism of toxicity of ‘Mustard Gas’ (or Nitrogen Mustard), a deadly chemical that was used in WW-I.
  41. Are polyfunctional alkylating agents CCS or CCNS?
    Polyfunctional alkylating agents are CCNS.
  42. What is the general mechanism of action for polyfunctional alkylating agents?
    The alkylating agents exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents, particularly DNA; alkylation of DNA and other cellular constituents lead to cell death.

    • The general mechanism of action of these drugs
    • involves intramolecular cyclization
    • to form an ethyleneimonium ion
    • that may directly or through formation of a carbonium ion transfer an alkyl
    • group to a cellular constituent (e.g., DNA).

    • The major site of alkylation within DNA is the
    • N7 position of guanine; however, other bases
    • are also alkylated to lesser degrees as well as phosphate atoms and proteins
    • associated with DNA.

  43. Why do polyfunctional alkylating agents create covalent bonds with DNA?
    All polyfunctional alkylating agents are electrophiles (highly electrophilic substances that are usually positively charged and eager to accept electrons...they are usually acidic).

    DNA, on the other hand has bases...it is neutrophilic.

    Therefore, when you combine an alkylating agent (electrophile) with DNA (nucleophile) = PARTY....Covalent bond!!
  44. Where can covalent binding occur in polyfunctional alkylating agents?
    Covalent binding interactions of the alkylating agents with DNA can occur on a single strand (monofunctional alkylating agents) or o both strands (bifunctional alkylating agents) of DNA through cross-linking (most major alkylating agents are bifunctional).
  45. Which alkylating agents are more effective: monofunctional or bifunctional? Why?
    Most major alkylating agents are bifunctional, which is good because they are also more effective than monofunctional alkylating agents.

    • The higher efficacy of bifunctional alkylating agents in cancer chemotherapy, as compared to monofunctional agents, is attributed to their ability to cross-link DNA.
  46. Which alkylating agents form a single covalent bond with DNA? Which form two covalent bonds with DNA?
    • Monofunctional alkylating agents: form a single covalent bond with DNA. These are not as effective as bifunctional because the cell can more easily repair the damage that just one bond causes.
    • Bifunctional alkylating agents: forms two covalent bonds...one bond with each strand of DNA, which is "cross linking" DNA. Therefore, these are sometimes called "cross-linkers." Most drugs on the market are bifunctional.
  47. What is the difference between methylation and alkylation?
    Methylation is distinct from alkylation in that it is specifically the transfer of one carbon, whereas alkylation can refer to the transfer of long chain carbon groups.
  48. What is the consequence of alkylated DNA?
    Alkylation of DNA results in miscoding or excision of alkylated residues; the latter leads to DNA strand breakage.
  49. In which phase of the cell cycle are cells most susceptible to polyfunctional alkylating agents?
    Although alkylating agents are CCNS, replicating cells (ie, cells in late G1 and S phases) are most susceptible to alkylation.
  50. What are the four mechanisms of resistance to alkylating agents?
    • 1) Increased capability to repair DNA.
    • 2) Decreased cell permeability to the drug.
    • 3) Increased production of glutathione which inactivates the electrophilic alkylating agent via conjugation.
    • 4) Increased glutathione S-transferase activity (the enzyme that catalyzes the glutathione conjugation reaction).
  51. What is glutathione?
    Glutathione is an endogenous tripeptide that protects us from toxic electrophiles (recall that electrophiles will form destructive covalent bonds with DNA).
  52. How does glutathione interfere with an electrophile and DNA forming a covalent bond?
    Glutathione will inactivate an electrophile (such as an alkylating agent) via conjugation.

  53. What enzyme catalyzes glutathione conjugation?
    Glutathione S-transferase is the enzyme that catalyzes the glutathione conjugation reaction.
  54. Is there cross resistance among the alkylating agents?
    Cross-resistance exists among the alkylating agents; however, there are exceptions to the rule depending on the specific type of tumor.
  55. What toxicities are associated with the alkylating agents?
    • The most common toxicities of the alkylating
    • agents include:
    • nausea
    • vomiting
    • bone marrow depression
  56. How is cyclophosphamide categorized?
    POLYFUNCTIONAL ALKYLATING AGENTS

    • Bis(chloroethyl)amines
    • Cyclophosphamide
    • Mechlorethamine
    • Chlorambucil
    • Melphalan
  57. What is the most widely used alkylating agent?
    Cyclophosphamide
  58. Is cyclophosphamide a bifunctional or monofunctional alkylating agent?
    bifunctional (meaning it forms two covalent bonds with DNA instead of just one covalent bond)
  59. How is cyclophosphamide administered?
    orally
  60. Does cyclophosphamide require bioactivation?
    Yes. Cyclophosphamide is relatively a less reactive alkylating agent; it requires activation to its cytotoxic forms by the cytochrome P450 enzyme system in the liver.

    In other words, cyclophosphamide has to be bioactivated by P450 enzymes in the liver.
  61. How does the liver protect itself from the cytotoxic effect of cyclophosphamide?
    The liver protects itself from the cytotoxic effect of cyclophosphamide by further metabolizing the active metabolites to inactive metabolites.
  62. What is the mechanism of action for cyclophosphamide?
    The active metabolites of cyclophosphamide are first delivered by the general circulation to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic (electrophilic) forms (phosphoramide mustard & acrolein) occurs.

    • In other words, cyclophosphamide is:
    • 1) catalyzed by P450 enzyme in the liver
    • 2) active metabolites formed in liver and 99% of the converted cyclophosphamide is dumped into immediate blood circulation
    • 3) 1% stays in liver and is converted quickly to inactive metabolites

  63. What are the inactive and active metabolites of cyclophosphamide called?
    • inactive metabolite: aldophosphamide
    • active metabolites: phosphoramide mustard & acrolein (electrophilic form of cyclophosphamide)
  64. How are the antimetabolites categorized?
    • ANTIMETABOLITES
    • 1) Methotrexate
    • 2) Pralatrexate
    • 3) Purine Antagonists
    • - 6-Thiopurines (Mercaptopurine or 6-MP)
    • - Fludarabine Phosphate
    • - Cladribine
    • 4) Pyrimidine Antagonists
    • - Fluorouracil or 5-FU
    • - Capecitabine
    • - Cytarabine
    • - Gemcitabine
  65. What is an antimetabolite?
    The antimetabolites are anticancer drugs that act on intermediary metabolism of proliferating cells. (If they work on proliferating cells, then they must be CCS remember).

    • They take advantage of a number of quantitative differences in metabolism that exist between
    • neoplastic cells and normal cells; these differences render tumor cells more susceptible to this particular class of anticancer drugs (the antimetabolites).

    In other words, antimetabolites inhibit nucleic acid synthesis in the cell by competing with natural cofactors in the cell. Therefore, antimetabolites are structurally related to intermediate cofactors in the cell. The end result is antimetabolites inhibit DNA and RNA.
  66. Are antimetabolites CCS or CCNS?
    Cell Cycle Specific (CCS)
  67. What is the mechanism of action for the antimetabolites?
    Antimetabolites are compounds which prevent the biosynthesis or utilization of normal cellular metabolites.

    • Nearly all clinically useful antimetabolites are structurally related to metabolites and
    • cofactors that are involved in the biosynthesis
    • of nucleic acids.

    Because of structural similarity, the antimetabolites are capable of antagonizing the normal cellular metabolites and cofactors and, as a result, inhibiting nucleic acid synthesis.
  68. How do the antimetabolites inhibit enzymes?
    Many of the antimetabolites are enzyme inhibitors; they inhibit enzymes by either:

    • 1) Binding to the catalytic site of the enzyme
    • (ie, compete with the normal substrate due to structural similarity).

    • 2) Binding to an allosteric regulatory site, particularly when the antimetabolite is structurally similar to the end product of a biosynthetic pathway
    • (ie, feedback control).
  69. Do antimetabolites need to be bioactivated?
    Some antimetabolites have to be bioactivated before they can exert their cytotoxic effect.
  70. How is methotrexate categorized?
    Methotrexate is an antimetabolite.
  71. What is methotrexate?
    Methotrexate is a folic acid antagonist.

  72. What is the mechanism of action for methotrexate?
    • Methotrexate is a folic acid antagonist that binds to the active catalytic site of dihydrofolate reductase (DHFR) enzyme, inhibiting the enzyme and interfering with the synthesis of tetrahydrofolic
    • acid (THF).

    The lack of THF inhibits the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby inhibiting the formation of DNA, RNA, and proteins.

    • Intracellular formation of polyglutamate derivatives during methotrexate therapy is important for its anticancer activity. The polyglutamates are selectively retained in cancer cells and have increased inhibitory effects on enzymes involved in folate metabolism, resulting in an increase in the duration of action of methotrexate.
  73. What is the step-by-step mechanism of action of methotrexate?
    • 1) Methotrexate inhibits an enzyme in folate metabolism: the dihydrofolate reductase enzyme (occasionally called "folate reductase").
    • 2) Tetrahydrofolic acid (THF) production is now blocked.
    • 3) THF is a precursor to:
    • - thymidylate
    • - purine nucleotides
    • - amino acid serine
    • - amino acid methionine
    • Therefore, since THF is blocked, so is the synthesis of all of the others.
    • 4) DNA synthesis is therefore blocked.
    • 5) Polyglutamate derivatives are formed and retained in cancer cells.
    • 6) Polyglutamate derivatives also inhibit enzymes in folate metabolism.
    • 7) Polyglutamate derivatives increase the duration of action of methotrexate.
  74. What are the two main effects of methotrexate?
    • 1) Methotrexate inhibits the biosynthesis of the dihydrofolate reductase enzyme, thus inhibiting the production of DNA in cancer and normal cells.
    • 2) Polyglutamates, which also inhibit folate metabolism enzymes, increase the cytotoxic effect of methotrexate.
  75. What mechanisms of resistance are there to methotrexate?
    • Tumor cell resistance to methotrexate has been attributed to:
    • 1) Decreased drug transport into the cell.
    • 2) Decreased polyglutamate formation.
    • 3) Synthesis of increased levels of DHFR via gene amplification.
    • 4) Altered DHFR with reduced affinity for methotrexate.
    • 5) Active efflux through activation of a MDR P170 glycoprotein transporter.
  76. What glycoprotein will facilitate active efflux of methotrexate out of the cell?
    MDR P170 glycoprotein transporter will facilitate active efflux of methotrexate.
  77. What toxicities are associated with methotrexate?
    • bone marrow depression (myelosuppression) *major toxicity
    • leucopenia
    • thrombocytopenia
  78. Since methotrexate inhibits the synthesis of purines and DNA in BOTH cancer cells and normal cells, is there any way to save the normal cells from the cytotoxic effects of methotrexate?
    Recall methotrexate inhibits the synthesis of purines and DNA in normal cells as well as cancer cells.

    To reverse these effects and rescue normal cells, one particular agent is administered: Leucovorin.

    Leucovorin (an important intermediate in the biosynthesis of purines and DNA) prevents the lethal effects of methotrexate on normal cells by rescuing the biosynthesis of purines and DNA.

    In addition, leucovorin inhibits the active transport of methotrexate into normal cells and stimulates its efflux out of normal cells.

    Leucovorin does not reach adequate concentrations in tumor cells; as a result, it will not rescue tumor cells.
  79. Why is Leucovorin called "Rescue Therapy"?
    • Leucovorin has three effects on normal cells when co-administered with methotrexate:
    • 1) Leucovorin is a downstream intermediate in the pathway to synthesizing purines and DNA (what methotrexate blocks). Therefore, by administering Leucovorin, we can bypass the step that methotrexate inhibits and continue on to make DNA and purines in normal cells.
    • 2) Leucovorin inhibits the active transport of methotrexate into normal cells.
    • 3) Leucovorin stimulates active efflux of methotrexate out of normal cells.
  80. Can "Rescue Therapy" save cancer cells, too?
    Leucovorin will not rescue cancer cells because leucovorin does not accumulate in cancer cells like it does in normal cells.
  81. How is mercaptopurine (6-MP) categorized?
    • ANTIMETABOLITES
    • Purine Antagonists
    • - 6-Thiopurines (Mercaptopurine or 6-MP)
    • - Fludarabine Phosphate
    • - Cladribine
  82. Must mercaptopurine be bioactivated?
    • 6-MP must be bioactivated first by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form 6-thioinosinic acid, which in turn inhibits a number of the enzymes involved in purine nucleotide interconversions. Consequently DNA synthesis is inhibited.
  83. What is the mechanism of action of mercaptopurine (6-MP)?
    • 1) hypoxanthine-guanine phosphoribosyl transferase (HGPRT) converts 6-MP to the active metabolite, which is 6-thioinosinic acid (nucleotide form).
    • 2) 6-thioinosinic acid (nucleotide form) inhibits several enzymes involved in purine nucleotide synthesis.
    • 3) DNA synthesis is ultimately inhibited.
  84. What are the two most common mechanisms of resistance of 6-MP?
    • decrease in HGPRT enzyme activity (the enzyme that converts 6-MP to the active metabolite)
    • increased levels of alkaline phosphatase (which inactivates 6-MP)
  85. What toxicities are associated with 6-MP?
    • myelosupprossion *main toxicity
    • hepatotoxicity
  86. What enzyme activates 6-MP? What enzyme deactivates 6-MP?
    • hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activates 6-MP to the active metabolite
    • xanthine oxidase enzyme deactivates 6-MP to the inactive metabolite
  87. Which drug is capable of enhancing 6-MP and why?
    6-MP is converted in the body to an inactive metabolite, 6-thiouric acid, by xanthine oxidase enzyme.

    The purine analog allopurinol is a potent inhibitor of xanthine oxidase.

    As a result, allopurinol is capable of enhancing the activity and toxicity of 6-MP.
  88. Why is allopurinol administered in chemotherapy patients?
    • Allopurinol is frequently administered with chemotherapy to cancer patients in order to prevent
    • hyperuricemia (which is caused by the release of purines into the general circulation following tumor cell lysis).

    Recall hyperuricemia is caused by killing a lot of cells, which causes an excess of purine bases into the circulation. This causes the metabolic proteins to convert the purine bases to uric acid, thus leading to hyperuricemia. Hyperuricemia can in turn lead to gout.
  89. What is hyperuricemia and what causes it?
    Recall hyperuricemia is a cause of killing a lot of cells, which causes an excess of purine bases into the circulation. This causes the metabolic proteins to convert the purine bases to uric acid, thus leading to hyperuricemia. Hyperuricemia can in turn lead to gout.
  90. How is fluorouracil (5-FU) categorized?
    • ANTIMETABOLITES
    • Pyrimidine Antagonists
    • - Fluorouracil
    • - Capecitabine
    • - Cytarabine
    • - Gemcitabine
  91. What is 5-FU?
    • 5-FU is a uracil analog.
  92. Does 5-FU need to be bioactivated?
    5-FU must be bioactivated first to ribosyl and deoxyribosyl nucleotide metabolites.

    • Its cytotoxicity is attributed to effects on both DNA- and RNA-mediated events.
  93. What is the mechanism of action of 5-FU?
    • DNA Inhibition
    • 5-FU is bioconverted to fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase enzyme and the synthesis of thymidylate. This results in inhibition of DNA synthesis.

    • RNA Inhibition
    • 5-FU is also bioconverted to fluorouridine triphosphate (FUTP), which is incorporated into RNA, where it interferes with RNA processing and mRNA translation.
  94. When speaking of 5-FU, what inhibits RNA synthesis? DNA synthesis?
    • 5-FUTP inhibits RNA synthesis
    • 5-FdUMP inhibits DNA synthesis
  95. What are toxicities associated with 5-FU?
    • myelosuppression
    • neurotoxicity
  96. How are the Vinca Alkaloids categorized?
    • NATURAL PRODUCTS
    • Vinca Alkaloids
    • - Vinblastine
    • - Vincristine
    • - Vinorelbine
  97. What are Vinca Alkaloids?
    Vinblastine and vincristine are plant alkaloids derived from the periwinkle plant (Vinca rosea).

    Vinorelbine is a semisynthetic vinca alkaloid.
  98. What are the similarities and differences between the Vinca Alkaloids?
    • Similarities
    • All vinca alkaloids exhibit the same mechanism of action and are closely related in their chemical structures.

    • Differences
    • Despite these similarities, there are differences among the vinca alkaloids; these differences are related to spectra of anticancer activity and toxicity.
  99. What is the mechanism of action of the vinca alkaloids?
    The vinca alkaloids cause depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle.

    They bind specifically to the microtubule protein tubulin in dimeric form.

    The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly, and depolymerization of the microtubules then occurs.

    Depolymerization of the microtubules results in mitotic arrest at metaphase (the M phase), dissolution of the mitotic spindle, and interference with chromosome segregation.
  100. What toxicities are associated with the vinblastine?
    • nausea
    • vomiting
    • bone marrow suppression
    • alopecia
  101. What toxicities are associated with vincristine?
    • neurotoxicity (including neuropathy, ataxia, seizures, coma)
    • myelosuppression *milder & less significant than in vinblastine
  102. Which drug is more toxic for myelosuppression: vinblastine or vincristine?
    Vinblastine has much more significant myelosuppression than what is found with vincristine.
  103. What toxicities are associated with vinorelbine?
    myelosuppression with neutropenia
  104. How are the Epipodophyllotoxins categorized?
    • NATURAL PRODUCTS
    • Epipodophyllotoxins
    • - Etoposide
    • - Teniposide
  105. What are etoposide and teniposide?
    Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum).

    • Both agents exhibit the same mechanism of action
    • and are closely related in their chemical structures.
  106. What is the mechanism of action of etoposide and teniposide?
    Etoposide and teniposide block cell division in the late S-G2 phase of the cell cycle. Therefore, these drugs are Cell Cycle Specific (CCS).

    • They inhibit topoisomerase II enzyme, which
    • results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme.
  107. What enzyme do Epipodophyllotoxins inhibit?
    Etoposide and teniposide, the epipodophyllotoxins, inhibit topoisomerase II enzyme.
  108. What are the toxicites of the epipodophyllotoxins?
    • nausea
    • vomiting
    • alopecia
    • bone marrow depression
  109. How are the camptothecins categorized?
    • NATURAL PRODUCTS
    • Camptothecins
    • - Topotecan
    • - Irinotecan
  110. What are the camptothecins?
    The camptothecins are natural products derived from a tree, Camptotheca acuminata.
  111. What is the mechanism of action for the camptothecins?
    They inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands.

    Inhibition of Topo I results in DNA damage.
  112. What are the toxicities associated with the camptothecins?
    • nausea
    • vomiting
    • diarrhea
    • myelosuppression
    • arthralgia (joint pain)
  113. Which drugs inhibit Topoisomerase I? Topoisomerase II?
    • Camptothecins (Topotecan & Irinotecan): inhibit Topoisomerase I
    • Epipodophyllotoxins (Etoposide & Teniposide) : inhibit Topoisomerase II
  114. How are the taxanes categorized?
    • NATURAL PRODUCTS
    • Taxanes
    • - Paclitaxel
    • - Docetaxel
  115. What are the taxanes?
    Paclitaxel (Taxol®) is a natural product derived from the pacific yew tree (Taxus brevifolia).

    Docetaxel is a semisynthetic taxane derived from the European yew tree (Taxus baccata).

    Both agents exhibit the same mechanism of action and are structurally related.
  116. What is the mechanism of action of the taxanes?
    The taxanes function as mitotic spindle poisons through high-affinity binding to microtubules with enhancement of tubulin polymerization.

    This promotion of microtubule assembly by the taxanes leads to inhibition of mitosis and cell division.
  117. What toxicities are associated with paclitaxel?
    • arrythmias
    • bone marrow depression
    • peripheral sensory neuropathy (nerve sensations)
  118. What toxicities are associated with docetaxel?
    • neurotoxicity
    • bone marrow depression (neutropenia)
  119. How are Epothilones (Ixabepilone) categorized?
    • NATURAL PRODUCTS
    • Epothilones
    • - Ixabepilone
  120. What are epothilones?
    Epothilones are cytotoxic macrolides (antibiotics) derived from bacterial fermentation.
  121. What does Ixabepilone (Ixempra®) treat?
    Ixabepilone (Ixempra®), a semisynthetic epothilone analog, has been approved for treatment of advanced breast cancer.
  122. What is the mechanism of action of epothilones?
    Like the taxanes, ixabepilone binds to tubulin of microtubules to induce microtubule polymerization and stabilization, which lead to arrest of cells in the G2-M phase of the cell cycle and the induction of apoptosis.

  123. Compare the epothilones to the taxanes.
    Epothilones and the taxanes bind differently to tubulin because they are not structurally related.

    As a result, the epothilones are not affected by the common mechanisms of resistance that affect the taxanes.

    Studies have shown that ixabepilone is active against tumors that are resistant to paclitaxel.
  124. Which has the least resistance: ixabepilone or paclitaxel?
    The epothilones are not affected by the common mechanisms of resistance that affect the taxanes.

    Studies have shown that ixabepilone is active against tumors that are resistant to paclitaxel.
  125. What are toxicities of ixabepilone?
    • peripheral sensory neuropathy
    • neutropenia (bone marrow depression)
    • *notice: same toxicities as the taxanes
  126. How are the anthracyclines categorized?
    • NATURAL PRODUCTS
    • Anthracyclines
    • - Doxorubicin
    • - Daunorubicin
    • - Idarubicin
    • - Epirubicin
  127. What are the most widely used cytotoxic anticancer drugs?
    • The anthracyclines are among the most widely used cytotoxic anticancer drugs. Daunorubicin and doxorubicin were the first agents in this class to be introduced.
  128. What are the four major effects or mechanisms of action that anthracyclines exhibit?
    • The anthracyclines exert their cytotoxic effect through four major mechanisms:
    • 1) Inhibition of topoisomerase II.
    • 2) High-affinity binding to DNA through intercalation, leading to inhibition of the synthesis of DNA and RNA as well as DNA strand breakage. In other words, the anthracyclines insert themselves (intercalate) between DNA bases in the double helix, then they act non-covalently via a hydrophobic bond to inhibit DNA.
    • 3) Binding to phospholipid cellular membranes to alter fluidity and ion transport.
    • 4) Generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process. Generation of free radicals has been shown to be the cause of the cardiac toxicity of the anthracyclines. In other words, the anthracyclines act as oxidizing agents in the presence of iron, and therefore produce reactive oxygen species (ROS), which are toxic and damage DNA.
  129. What is ‘intercalation’ and what exactly is the difference between intercalation and covalent binding?
    Intercalation is the reversible inclusion of a molecule (or group) between two other molecules (or groups). In other words, a molecule is reversibly inserting itself between two other molecules.

    Covalent binding, in contrast, is irreversible.
  130. Why are anthracyclines able to intercalate with DNA?
    Anthracyclines have aromatic rings that are flat!

    Therefore, because the molecular structure is basically 2-D (rather than 3-D), the anthracyclines can insert themselves (like a piece of paper) between the DNA bases on the double helix structures of DNA.

    There, the anthracyclines will interact non-covalently (rather than covalently) via hydrophobic bonds to inhibit DNA.
  131. Which drugs inhibit Topoisomerase I? Topoisomerase II?
    • Inhibit Topoisomerase I
    • Camptothecins (Topotecan & Irinotecan)

    • Inhibit Topoisomerase II
    • Epipodophyllotoxins (Etoposide & Teniposide)
    • Anthracyclines (Doxorubicin, Daunorubicin, Idarubicin, Epirubicin)
  132. What are the major toxicities of the anthracyclines?
    • myelosuppression with neutropenia
    • cardiotoxicity
  133. What are the two forms of cardiotoxicity observed during anthracycline therapy?
    • Two forms of cardiotoxicity are observed during anthracycline therapy:
    • 1) Acute Cardiotoxicity which occurs
    • within the first 2-3 days of therapy and is characterized by arrhythmias and myocarditis. This form of cardiotoxicity is usually transient and is asymptomatic in most cases.
    • 2) Chronic Cardiotoxicity which results in a dose-dependent, dilated cardiomyopathy associated with heart failure. This form of cardiotoxicity is caused by increased production of free radicals within the myocardium.
  134. With anthracycline therapy, which type of cardiotoxicity is usually transient and/or asymptomatic?
    Acute Cardiotoxicity
  135. With anthracycline therapy, which type of cardiotoxicity usually occurs within the first 2-3 days of therapy?
    Acute Cardiotoxicity
  136. With anthracycline therapy, which type of cardiotoxicity is associated with heart failure?
    Chronic Cardiotoxicity
  137. With anthracycline therapy, which type of cardiotoxicity is associated with free radical production in the myocardium?
    Chronic Cardiotoxicity
  138. What three things can reduce the incidence of cardiotoxicity when administering anthracycline therapy?
    • 1) A decrease in the dose
    • 2) The use of slow, continuous infusion
    • 3) The use of Dexrazoxane (Zinecard®, Totect®) has been shown to protect against the cardiotoxicity of anthracyclines because dexrazoxane is a potent iron-chelating agent (like tetracylines). If iron is suppressed through chelation, then there are no free radicals produced from the iron!
  139. Why is dexrazoxane (Zinecard®, Totect®) used to reduce cardiotoxicity when administering anthracycline therapy?
    The use of Dexrazoxane (Zinecard®, Totect®) has been shown to protect against the cardiotoxicity of anthracyclines because dexrazoxane is a potent iron-chelating agent (like tetracylines). If iron is suppressed through chelation, then there are no free radicals produced from the iron!
  140. How is mitomycin categorized?
    • NATURAL PRODUCTS
    • Mitomycin
  141. What is mitomycin?
    Mitomycin is a CCNS alkylating agent.
  142. Is mitomycin CCS or CCNS?
    Mitomycin is Cell Cycle Nonspecific (CCNS).
  143. What is the mechanism of action for mitomycin?
    Mitomycin is metabolically activated via an enzymatic reduction reaction to generate an alkylating electrophilic species that is capable of cross-linking DNA.

  144. What type of reaction do hypoxic tumor stem cells favor: reductive or oxidative reaction?
    Hypoxic tumor stem cells of solid tumors exist in an environment conducive to reductive reactions and, as a result, are more sensitive to the cytotoxic effects of mitomycin than normal cells and oxygenated tumor cells.
  145. What are major toxicities of mitomycin?
    • thrombocytopenia
    • leucopenia
  146. How is bleomycin categorized?
    • NATURAL PRODUCTS
    • Bleomycin
  147. What are the two binding domains on bleomycin?
    Bleomycin is a peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule.
  148. What is bleomycin? CCS or CCNS?
    Bleomycin is a CCS anticancer drug that causes accumulation of cells in the G2 phase of the cell cycle.
  149. What is the mechanism of action of bleomycin?
    It acts by binding to DNA, which results in single strand and double-strand breaks following free radical formation; this leads to inhibition of DNA synthesis.
  150. How is DNA fragmented with bleomycin?
    The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe (II) complex and leads to chromosomal aberrations.
  151. What is the dose-limiting toxicity associated with bleomycin?
    • The dose-limiting toxicity for bleomycin is pulmonary toxicity which is characterized
    • by:
    • pneumonitis with cough
    • dyspnea
    • infiltrates
  152. What increases the risk of pulmonary toxicity in bleomycin? Can pulmonary toxicity cause death?
    • The incidence of pulmonary toxicity is increased:
    • 1) in patients older than 70 years of age
    • 2) with cumulative doses greater than 400 units

    In rare cases, pulmonary toxicity can be fatal.
  153. How are Tamoxifen & Raloxifene categorized?
    • HORMONAL AGENTS
    • Antiestrogens
    • - Tamoxifen (SERM)
    • - Raloxifene (SERM)
    • - Fulvestrant (SERD)
  154. What is Tamoxifen?
    • Tamoxifen is a selective estrogen-receptor
    • modulator (SERM).

    • Tamoxifen has estrogen-agonist effects in bone and uterus; it has anti-estrogen effects in
    • the breast tissue.
  155. What is unique about Tamoxifen?
    Tamoxifen has estrogen-agonist effects in bone and uterus; it has anti-estrogen effects in the breast tissue.
  156. What does tamoxifen treat?
    The anti-estrogen tamoxifen has proved to be extremely useful for the treatment of both early-stage and metastatic breast cancer. It is also used as a chemopreventive agent in women at high risk for breast cancer.
  157. Is tamoxifen first line?
    Yes. Tamoxifen is first line of therapy.
  158. How is tamoxifen administered?
    It is given orally.
  159. How does raloxifene differ from tamoxifen?
    Raloxifene, a related SERM, differs from tamoxifen mainly in having anti-estrogen effects in the uterus.

    Recall that tamoxifen has estrogen agonist effects in the uterus.
  160. Which drug is better: tamoxifen or raloxifene?
    • Tamoxifen and raloxifene are both indicated for
    • and equally effective in the prevention of breast cancer in women at high risk for development of the disease (in the ‘STAR’ trial, both drugs reduced the risk of developing invasive breast cancer by about 50% in postmenopausal women who are at increased risk of developing the disease).

    • Raloxifene may have a more favorable adverse-effect profile, with fewer thromboembolic events (known toxicities of SERMs, including deep vein
    • thrombosis and pulmonary embolism) and less uterine hyperplasia (endometrial cancer) when compared with tamoxifen.
  161. What is the mechanism of action of tamoxifen?
    Tamoxifen acts as a competitive partial agonist (ie, an antagonist) of estrogen and binds to the estrogen receptors of estrogen-sensitive tumors.
  162. Compare tamoxifen to estradiol (estrogen), the main sex hormone in women.
    Tamoxifen has a much longer biologic half-life (7-14 days) than estradiol.

    Tamoxifen has a tenfold lower affinity for the estrogen receptor than does estradiol, indicating the importance of ablation (removal) of endogenous estrogen for optimal antiestrogen effect.
  163. Is there a way to clinically enhance the effects of tamoxifen?
    Remove endogenous estrogen so tamoxifen does not have to compete with estrogen for the binding site. Tamoxifen has tenfold lower affinity for the estrogen receptor.
  164. Does tamoxifen have to be bioactivated?
    Yes. Tamoxifen is bioactivated in the body by CYP2D6.
  165. What class of drugs may reduce the efficacy of tamoxifen?
    Inhibitors of CYP2D6, such as the selective serotonin reuptake inhibitors (SSRIs), may lower the success rate of tamoxifen in preventing recurrence of breast cancer.
  166. Why are drug interactions a concern with tamoxifen therapy?
    The use of SSRIs is common in women taking tamoxifen for breast cancer, both to treat depression and to decrease hot flashes.
  167. Which SSRIs are potent inhibitors of CYP2D6 (the enzyme that metabolizes tamoxifen)? Which are weak inhibitors of CYP2D6?
    • SSRIs that are potent inhibitors of CYP2D6 are: Fluoxetine(Prozac®)
    • Paroxetine (Paxil®)
    • Sertraline (Zoloft®) inhibits CYP2D6 to a lesser extent

    • SSRIs that are weak inhibitors of CYP2D6 are: Citalopram (Celexa®)
    • Escitalopram (Lexapro®)
  168. If a woman needs to take an SSRI while on tamoxifen, what might be the best choice?
    For women who need to take a SSRI with tamoxifen, citalopram or escitalopram might be the safest choice.

    Recall these SSRIs are weak inhibitors of CYP2D6, the same enzyme that metabolizes tamoxifen to its active form.
  169. What toxicities are associated with tamoxifen?
    Tamoxifen is well tolerated; its toxicities are generally mild and include menopausal symptoms and thromboembolic events (deep vein thrombosis and pulmonary embolism).

    Tamoxifen therapy increases the risk/incidence of estrogen-sensitive endometrial hyperplasia and cancer (uterine cancer).
  170. How is fulvestrant categorized?
    • HORMONAL AGENTS
    • Antiestrogens
    • - Tamoxifen (SERM)
    • - Raloxifene (SERM)
    • - Fulvestrant (SERD)
  171. What is fulvestrant?
    Fulvestrant is a selective estrogen-receptor downregulator (SERD).
  172. What does fulvestrant treat?
    Fulvestrant was approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that has progressed despite first-line anti-estrogen therapy such as tamoxifen.
  173. Is fulvestrant first line?
    No. Fulvestrant is second line of therapy.
  174. How do SERMs compare to SERDs?
    • SERDs, unlike SERMs, are devoid of any
    • estrogen-agonist activity. SERDs are ‘pure anti-estrogens’ or ‘pure ER-antagonists’.

    SERDs are expected to have a better safety profile, faster onset, and longer duration of action than the SERMs.
  175. Are SERDs agonists or antagonists?
    SERDs are antagonists of estrogen receptors.

    SERDs, unlike SERMs, are devoid of any estrogen-agonist activity. SERDs are ‘pure anti-estrogens’ or ‘pure ER-antagonists’.
  176. Which drugs are better: SERDs or SERMs?
    • SERDs are expected to have:
    • a better safety profile
    • faster onset
    • longer duration of action
    • ...than the SERMs
  177. Which has a higher binding affinity for estrogen: fulvestrant or tamoxifen?
    Fulvestrant is a steroidal anti-estrogen that binds to the ER (estrogen receptor) with an affinity more than 100 times that of tamoxifen.
  178. What is the mechanism of action for fulvestrant?
    Binding of fulvestrant to the ER (estrogen receptor) sterically hinders receptor dimerization, leading to inhibition of receptor dimerization and an increase in ER (estrogen receptor) degradation (turnover).
  179. Does fulvestrant decrease the number (down regulate) the number of estrogen receptors? Does tamoxifen?
    Unlike tamoxifen, fulvestrant reduces the number of ER molecules in cells, both in vitro (test tube) and in vivo (within the living) (ie, downregulation of ER).
  180. Why might fulvestrant work against a cancer that is resistant to tamoxifen?
    Recall that fulvestrant has a different mechanism of action than tamoxifen and down-regulates estrogen receptors.

    • ER down-regulation abolishes ER-mediated transcription, completely suppressing
    • the expression of estrogen-dependent genes.

    This likely explains why fulvestrant is effective against tamoxifen-resistant breast cancer.
  181. What toxicities are associated with fulvestrant?
    Fulvestrant is generally well tolerated.

    • Most common adverse effects of fulvestrant include:
    • nausea
    • vasodilation (hot flashes)
    • headache
  182. How are Flutamide, Bicalutamide and Nilutamide categorized?
    • HORMONAL AGENTS
    • Antiandrogens
    • - Flutamide
    • - Bicalutamide
    • - Nilutamide
  183. What are the antiandrogens?
    They are nonsteroidal antiandrogen agents that bind to the androgen receptors of androgen-sensitive tumors and block androgen effects.
  184. What do the antiandrogens treat?
    They are used, in combination with radiation therapy, for the treatment of early-stage prostate cancer and metastatic prostate cancer.
  185. Are the antiandrogens used in combination?
    The antiandrogens are used in combination with radiation therapy.
  186. What toxicities are associated with the antiandrogens?
    • Toxicities of the antiandrogen agents include:
    • mild nausea
    • hot flashes
    • gynecomastia
    • variable degrees of decreased libido and potency
  187. How are the GnRH agonists categorized?
    • HORMONAL AGENTS
    • Gonadotropin-Releasing Hormone Agonists
    • - Leuprolide
    • - Goserelin
    • - Triptorelin
  188. What does GnRH stand for?
    Gonadotropin Releasing Hormone
  189. What are the GnRH agonists?
    The GnRH agonists, which include Leuprolide, Goserelin, Triptorelin, are synthetic peptide analogs of gonadotropin-releasing hormone (GnRH).
  190. What do GnRH agonists treat?
    They are used for the treatment of advanced prostate cancer and as part of neoadjuvant therapy of early-stage prostate cancer.
  191. What does neoadjuvant mean?
    Neoadjuvant therapy is the administration of therapeutic agents before the main treatment.
  192. What is the mechanism of action of GnRH agonists?
    They function as GnRH agonists and are more potent than the natural hormone.

    They stimulate a transient release of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH), followed by inhibition of the release of FSH and LH. This leads to suppression of testosterone production in the testes.
  193. What is more potent: the natural Gonadotropin Releasing Hormone, or the GnRH agonists?
    The GnRH agonists are more potent than the natural hormones.
  194. How much does GnRH agonists suppress testosterone and how long does it take to work?
    In men, 2-4 weeks of GnRH agonist therapy results in castration levels of testosterone.
  195. What is an important complication of using GnRH agonists?
    One important complication with GnRH agonist therapy is a transient flare of disease which results from the initial surge of LH and FSH (and the transient initial increase in testosterone levels).
  196. Is there any way to get around the initial surge of testosterone created by GnRH agonists?
    This initial surge of testosterone can be avoided by temporary (2-4 weeks) administration of androgen receptor blockers or by the use of GnRH antagonists.
  197. What toxicities are associated with GnRH agonists?
    • hot flashes
    • impotence
    • gynecomastia
  198. What disease states are significantly increased by GnRH agonists?
    In addition, GnRH agonists significantly increase the risk of diabetes and heart disease (MI, stroke, and sudden death) among men who use these drugs (i.e., men who use androgen deprivation therapy) to treat prostate cancer.
  199. What hormone do GnRH agonists deprive?
    The androgens (sex hormones) in men, which is mainly testosterone.
  200. How are the GnRH antagonists categorized?
    • HORMONAL AGENTS
    • Gonadotropin-Releasing Hormone Antagonists
    • - Degarelix
  201. What is degarelix?
    Degarelix (Firmagon®) is a synthetic decapeptide GnRH receptor antagonist.
  202. What is degerelix used to treat?
    Degerelix is used for rapid medical castration of men with advanced prostate cancer.
  203. What is the mechanism of action for degerelix?
    It binds reversibly to the GnRH receptor in the anterior pituitary gland. As a result, it inhibits the release of gonadotropins (LH and FSH), which in turn suppresses testosterone production in the testes.
  204. Does degerelix bind reversibly or irreversibly?
    Degerelix binds reversibly.
  205. What are gonadotropins?
    • Follicle Stimulating Hormone (FSH)
    • Luteinizing hormone (LH)
  206. Is there any advantage to using GnRH agonists vs. GnRH antagonists?
    GnRH antagonist therapy rapidly reduces serum testosterone levels without the transient initial increase observed with GnRH agonist therapy.

    Other than avoidance of the initial flare of disease, GnRH antagonist therapy offers no advantage compared with GnRH agonists.
  207. What toxicities are associated with degerelix?
    • hot flashes
    • weight gain
    • increase in hepatic transaminases (liver enzymes)
  208. What are hepatic transaminases?
    • hepatic means "of the liver"
    • transaminase is an enzyme that catalyzes an amine reaction
    • therefore, hepatic transaminases are liver enzymes
  209. What could be a serious consequence of long-term androgen deprivation therapy?
    Long-term androgen deprivation therapy can prolong the QT interval, which could be problematic in patients taking other drugs that also prolong the QT interval.
  210. How are aromatase inhibitors categorized?
    • HORMONAL AGENTS
    • Aromatase Inhibitors
    • - Aminoglutethimide
    • - Anastrozole
    • - Letrozole
    • - Exemestane
  211. What does the aromatase enzyme do?
    Aromatase enzyme converts the adrenal androgen androstenedione to estrone.
  212. Where does the aromatization reaction occur?
    This aromatization of an androgenic precursor (androstenedione) into an estrogen (estrone) occurs in body fat.
  213. What is estrone?
    Estrone (E1, and also oestrone) is an estrogenic hormone secreted by the ovary as well as adipose tissue.

    Estrone is one of several natural estrogens, which also include estriol and estradiol. Estrone is the least abundant of the three hormones; estradiol is present almost always in the reproductive female body, and estriol is abundant primarily during pregnancy.
  214. Why might estrogens be involved in breast cancer?
    Since estrogens promote the growth of breast cancer, estrogen synthesis in adipose tissue can be important in breast cancer growth in postmenopausal women.
  215. What are aromatase inhibitors?
    Anticancer aromatase inhibitors act as inhibitors of estrogen synthesis in adipose tissue and are used for the treatment of breast cancer in postmenopausal women.
  216. What specialty population would aromatase inhibitors be used on?
    postmenopausal women
  217. How is aminoglutethimide categorized?
    • HORMONAL AGENTS
    • Aromatase Inhibitors
    • - Aminoglutethimide
    • - Anastrozole
    • - Letrozole
    • - Exemestane
  218. What is aminoglutethimide?
    Aminoglutethimide is a nonsteroidal inhibitor of the aromatase enzyme.
  219. What two things does aminoglutethimide inhibit?
    • 1) estrogen synthesis in adipose tissue
    • 2) adrenal steroidogenesis (corticosteroid synthesis), which include glucocorticoids and mineralcorticoids
  220. What are the corticosteroids?
    • Coricosteroids are steroid hormones produced in the adrenal cortex.
    • Glucocorticoids (cortisol)
    • Mineralcorticoids (aldosterone)
  221. Which drug is aminoglutethimide normally administered with and why?
    It is normally administered with hydrocortisone to prevent symptoms of adrenal insufficiency.
  222. What toxicities are associated with aminoglutethimide?
    • adrenal insufficiency
    • myelosuppression
  223. How is anastrozole categorized?
    • HORMONAL AGENTS
    • Aromatase Inhibitors
    • - Aminoglutethimide
    • - Anastrozole
    • - Letrozole
    • - Exemestane
  224. What is anastrozole?
    Anastrozole is a selective nonsteroidal inhibitor of aromatase.
  225. Is anastrozole selective or nonselective?
    selective
  226. What does anastrozole inhibit?
    aromatase
  227. What does anastrozole treat?
    It is used for the treatment of postmenopausal women with metastatic breast cancer that is ER-positive (ER = estrogen receptor), as well as women whose tumors have progressed while on tamoxifen therapy. It is also used as adjuvant therapy of postmenopausal women with hormone-positive, early-stage breast cancer.
  228. What three different circumstances might anastrozole be used in?
    • ER positive metastatic breast cancer
    • adjuvant therapy for ER positive early stage breast cancer
    • second line therapy for those that have been on tamoxifen
  229. How is anastrozole different than aminogluthimide?
    Unlike aminoglutethimide, anastrozole has no inhibitory effect on adrenal glucocorticoid or mineralocorticoid synthesis.
  230. What are toxicities of anastrazole?
    • hot flashes
    • mild nausea
    • arthralgias (joint pain)
  231. Which other selective aromatase inhibitor is extremely similar to anastrazole?
    Letrozole is another selective aromatase inhibitor that has the same mechanism of action, toxicities, and clinical indications as anastrozole.
  232. How is exemestane categorized?
    • HORMONAL AGENTS
    • Aromatase Inhibitors
    • - Aminoglutethimide
    • - Anastrozole
    • - Letrozole
    • - Exemestane
  233. What is exemestane?
    Exemestane is a steroidal hormonal agent that binds to and irreversibly inactivates the aromatase enzyme.
  234. Does exemestane bind reversibly or irreversibly?
    irreversibly
  235. What does exemestane treat?
    It is indicated for the treatment of advanced breast cancer in postmenopausal women whose tumors have progressed on tamoxifen therapy.
  236. Is exemestane first line?
    No. Exemestane is second line after tamoxifen.
  237. Is there any cross resistance between exemestane and the nonsteroidal aromatase inhibitors?
    There is no cross-resistance between exemestane and the nonsteroidal aromatase inhibitors.
  238. What are the toxicities of exemestane?
    • hot flashes
    • mild nausea
    • headache
  239. How is Imatinib categorized?
    • PROTEIN TYROSINE KINASE INHIBITORS
    • - Imatinib
    • - Dasatinib
    • - Sunitinib
    • - Sorafenib
    • - Gefitinib
    • - Erlotinib
    • - Lapatinib
    • - Nilotinib
    • - Temsirolimus
    • - Everolimus
    • - Pazopanib
  240. What are protein kinases?
    Protein kinases are critical components of signal transduction pathways that transmit information concerning extracellular or cytoplasmic conditions to the nucleus, thereby influencing gene transcription and/or DNA synthesis.
  241. What are Tyrosine kinases? What two categories are they classified into?
    • Tyrosine kinases are classified into:
    • 1) proteins that have an extracellular ligand binding domain (receptor tyrosine kinases)
    • 2) enzymes that are confined to the cytoplasm and/or nuclear cellular compartment (nonreceptor tyrosine kinases)
  242. Why would tyrosine kinase be a good target for anticancer therapy drugs?
    Abnormal activation of specific protein tyrosine kinases has been demonstrated in many human cancers, making them attractive molecular targets for cancer therapy.
  243. What are the three tyrosine kinases that Imatinib inhibits?
    • Imatinib has inhibitory activity against:
    • 1) the platelet-derived growth factor receptor (PDGFR) tyrosine kinase
    • 2) the cytoplasmic ABL tyrosine kinase
    • 3) the receptor tyrosine kinase KIT
  244. What does Imatinib treat?
    • Imatinib is effective in treating cancers in which the
    • ABL, KIT, or PDGFR have dominant roles in driving the proliferation of the tumor.

    This dominant role is defined by the presence of a mutation that results in constitutive (constant) activation of the kinase.
  245. What is a constitutive kinase?
    Constitutive means it is constantly active, so a constitutive kinase or protein would be constantly turned on.
  246. What specific types of cancer will Imatinib treat?
    • Imatinib shows remarkable therapeutic efficacy in
    • patients with:
    • chronic myelogenous leukemia (CML) gastrointestinal stromal tumors (GISTs)
    • chronic myelomonocytic leukemia (CMML)
    • hypereosinophilic syndrome (HES)
  247. How is imatinib administered?
    orally
  248. Is there any tumor resistance to imatinib?
    Acquired resistance to imatinib results predominantly from mutations in the kinase domain.
  249. What toxicities are associate with imatinib?
    • nausea
    • vomiting
    • edema
    • muscle cramps

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