Anti-Neoplastic Agents III

  1. Name the two major groups of compounds that disrupt cell
    division by targeting tubulin. In
    general, how do the two groups differ?
    • Vinca
    • alkaloids & Taxanes; Vinca alkaloids bind to β-tubulin and prevents polymerization w/α-tubulin and formation of microtubules while
    • taxanes

    bind and cause aggregation.
  2. Of the four active dimeric alkaloids, which two have been
    used clinically for a number of leukemias, lymphomas and testicular cancer.
    Vinblastine & vincristine
  3. ____________________ is able to dissolve microtubules.
  4. In vinca alkaloids, cell division is arrested in which
  5. What happens to the cells after vinca alkaloids bind β-tubulin?
    What is the potential problem of this?
    • Cells undergo an apoptotic-like process in which the
    • duplicated chromosomes disperse throughout the cytosol in clumps. Potential problems occur because neurons have
    • large amounts of microtubules for transport.
  6. _______________ results in increased levels of the efflux
    protein P-glycoprotein in vinca alkaloid resistance. This can be overcome by _________________.
    Gene amplification; calcium channel blockers
  7. What can mutations in β-tubulin lead to with vinca alkaloids?
    • Decreased binding of the vinca alkaloids to β-tubulin
    • (reduces effectiveness)
  8. List the primary toxicities associated with vinca alkaloids.
    • Myelosuppression, neurological toxicity (loss of DTRs,
    • numbness and tingling in extremities), rarely vocal cord paralysis &
    • extraocular muscle function
  9. What are the vinca alkaloids a standard component of
    regimens for?
    Pediatric leukemias, lymphomas, and solid tumors
  10. What is the CHOP regimen used for?
    • (cyclophoph-amide,
    • doxorubicin, prednisone) – very effective against large cell non-Hodgkins
    • lymphoma
  11. Name the solid tumors of childhood vincristine is used for.
    Wilms tumor, neuroblastoma, rhabdomyosarcoma
  12. Which vinca alkaloid is more effective against adult
    testicular cancer, bladder cancer and Hodgkins disease?
  13. _______________ is active against non-small cell lung cancer
    and breast cancer.
  14. IV infusions of vinblastine can cause what serious injury?
  15. Vinblastine used to be used with belomycin and cisplatin for
    testicular cancer, but now _________ is used.
  16. What is vinblastine active against?
    • Component of standard ABVD (decarbazine, vinblastine,
    • doxorubicin & belomycin) regimen for Hodgkin disease. Active against adult Kaposi sarcoma,
    • neuroblastoma & histiocytosis X.
  17. Vincrisinte can be used with ____________ for remission of
    childhood leukemia.
  18. Adults are more prone to which severe toxicity with
    vincristine compared to children?
    Severe neurotoxicity
  19. _____________ formulation of vincristine is used in large-cell
    lymphoma which produces less neurotoxicity.
  20. Vincrisitine can produce both _________ _________(2) and
    _________, both of which are reversible.
    Severe constipation; alopecia
  21. Do taxanes bind to the same or different site as the vinca
  22. Name a synthetic version of paclitaxel.
  23. Paclitaxel is administered in 50% EtOH and 50%
    polyehtoxylated castor oil because it has _____ ________(2). In doing so, this enhances the potential for
    Poor solubility; hypersensitivity reactions
  24. In order to avoid hypersensitivity reactions with paclitaxel
    administered in 50% EtOH and 50% polyethoxylated castor oil, what are patients
    pretreated with?
    • H1 receptor & H2 receptor antagonists and a
    • glucocorticoid.
  25. How do taxanes arrest mitosis?
    • By forming aberrant microtubular structures due to excessive
    • aggregation.
  26. What drugs can inhibit the effectiveness of taxols?
    • Drugs that inhibit cell-cycle progression prior to
    • microtubule formation.
  27. What are patient given to overcome bone marrow suppression
    caused by paclitaxel?
  28. Why does docetaxel produce greater neutropenia and fluid
    Excess ADH release
  29. Taxanes undergo extensive metabolism by ________ w/ some ________,
    so little parent excreted.
    CYP2C8; CYP3A4
  30. _____________ is used w/estramustine for treatment of
    hormone-refractory prostate cancer.
  31. _______ are central drugs for treatment of metastatic
    breast, ovarian, lung and head & neck cancers.
  32. ___________ more leukopenia & peripheral edema; while ______________
    more hypersensitivity, muscle ache and neuropathy.
    Docetaxel; paclitaxel
  33. Camptothecin analogs target
    _____________________ ___ a nuclear enzyme that relieve torsional stress
    in supercoiled DNA.
    Topoisomerase I
  34. Anthacycline drugs target _________________.
    Topoisomerase II
  35. Topoisomerase I binds to DNA and makes a _____________ ________ (2) break via
    a reversible transesterification rxn such that an enzyme tyrosine becomes
    covalently bound to a 3’-phosphate of the DNA.
    Single Strand
  36. In addition to making a single strand break, topo-I does
    Reseals the DNA
  37. _______________
    ____________ bind and stabilize the DNA-topo-I complex. This results in
    single-strand breaks that are not resealed.
    Camptothecin analogs
  38. Single strand breaks caused by camptothecin analogs leads to
    __________ _________ breaks during replication.
    Double strand
  39. Camptothecin analogs require cells to be cycling through
    what cell phase to be sensitive to them?
  40. Extensive double strand break formation may induce
  41. Increased expression of topo-I could produce resistance or
    decreased expression due to __________ __________ (2)
    Promoter methylation
  42. Mutations to topo-I to reduce camptothecin binding have been
    shown _______ _________(2).
    In vitro
  43. Which camptothecin
    analog is indicated for treatment of previously treated ovarian and small cell
    lung cancer?
  44. _____________ is indicated for advanced colorectal cancer
    either w/5-FU (no prior failure) or without (prior 5-FU failure).
  45. What is the dose-limiting toxicity of topotecan?
    • Neutropenia w/or without thrombocytopenia (mucositis &
    • diarrhea may become dose limiting)
  46. What is irinotecan’s primary dose-limiting toxicity?
    Delayed diarrhea (myelosuppresion is second most common)
  47. List several classes of antibiotics and bacterial
    fermentation products shown to have antitumor activity.
    • Actinomycin D, Daunorubicin and analogs, Mitoxantrone,
    • Bleomycins, Mitomycin
  48. ___________ ____ (2) has activity against solid tumors of
    children and choriocarcinoma.
    Actinomycin D
  49. Actinomycin D is a __________________ that produces
    yellow-red color.
  50. What does the actinomycin molecule intercalate between which
    blocks transcription of RNA?
    Adjacent G-C base pairs
  51. _____ dependent ____ polymerases more sensitive compared to _____
    dependent ______ polymerases.
  52. True/False Actinomycin D is a very potent inhibitor of
    resting cells.
    False; very potent inhibitor of rapidly diving cells.
  53. Two important side effects of actinomycin are ________ and
    __________ _________ (2).
    Alopecia; extravasation injury
  54. List indications for Actinomycin D.
    • Childhood Wilm’s tumor where potentially curative
    • (extensively), active against Kaposi’s sarcom, Ewing’s tumor and soft tissue
    • sarcomas.
  55. Patients on Actinomycin D may experience bone marrow
    suppression with ___________.
  56. Anthracycline antibiotics are Significant antitumor drugs
    derived from the fungus __________________ _________ ____ ______
    • Streptococcus
    • peucetius var. caesius
  57. Anthracycline antibiotics form a tripartite complex with
    __________________ ___ & ____.
    Topoisomerase II; DNA
  58. Topo-II produces ___________ ____________ breaks to relieve
    torsional stress on the DNA.
    Double strand
  59. Formation of the tripartite complex prevents __________ and
    produces multiple double-strand breaks.
  60. _______________________ can produce can produce semiquinone
    free radicals that can produce several reactive oxygen species.
  61. What leads to anthracycline antibiotics’ major toxicity of
    cardiac injury?
    Production of reactive oxygen species
  62. List the multiple resistance mechanisms seen in
    anthracycline antibiotics.
    P-glycoprotein and MRP induction

    ↑ glutathione peroxidase activity

    ↓ topo-II activity

    • ↑ double strand repair capability (error-prone can still
    • end up with apoptotic cell)
  63. All anthracyclines need to be converted to what for
    Alcohol intermediate
  64. Idarubicin replaced ___________ for treatment of AML
    generally in combination w/Ara-C.
  65. __________ is active against malignant lymphomas, but also
    solid tumors including breast.
    Doxorubicin (Adriamycin)
  66. What is the major dose-limiting toxicity for anthracyclines?
    • Myelosuppression w/leukopenia followed by thrombocytopenia
    • and anemia.
  67. Name three side effects that are common in anthracycline
    Stomatitis, GI distress and alopecia
  68. Cardiomyopahty is a serious long-term toxicity for
    anthracycline antibiotics. List the acute
    and chronic effects.
    • Acute: ST and T-wave changes can occur but these are
    • reversible.

    • Chronic: cumulative dose-related toxicity can produce a CHF
    • that is not responsive to digitalis. Mortality approaches 50%. Risk increases
    • to >20% of patients w/ total doses greater than 550 mg/m2
  69. ___________ is used for AML has less ability to produce
    quinone-type free radicals and has less cardiotoxicity, but similar other
  70. Bleomycins are antibiotics purified from _________________
    ___________ (2) fermentation products
    Streptococcus verticillus
  71. Bleomycins A2 and B2 are what kind of
    Copper chelating peptides
  72. What are belomycins active against?
    • Squamous carcinoma of the cervix; lymphomas & testicular
    • cancer.
  73. Belomycins are minimally _______ and _______________________
    so can be combined w/other agents without potentiating these toxicities
    Myelosuppressive; immunosuppressive
  74. Bleomycin causes oxidative damage to the ________________ of
    ___________ and other nucleotides.
    Deoxyribose; thymidylate
  75. The oxidative damage from belomycin leads to single &
    double-strand breaks with cells accumulating at which phase of the cell cycle?
  76. During belomycin treatment cells can show chromosomal
    aberrations w/ ________ _______ (2), _______________ and translocations.
    Chromatid breaks; fragmentation
  77. Bleomycin can cause DNA damage involving ______ and ________
    in which the metal-drug complex acts as a ______________ _____________.
    O2; Fe++; ferrous oxidase
  78. Why is toxicity of bleomycin see in the skin and lungs?
    • It is degraded by a cellular hydrolase present in the liver,
    • but not in the skin or lungs.
  79. Bleomycin is effective against ____________ _______ tumors
    of the testes and ovaries.
    Germ cell
  80. In combination with cisplatin, bleomycin is curative for
    which type of cancer?
  81. Used in the ABVD regimen for __________ ___________ (2) and
    given intrapleurally for _________ __________ _________(3).
    Hodgkin’s disease; malignant pleural effusions
  82. Bleomycin can be instilled into the bladder to treat
    ________ __________.
    Bladder carcinoma
  83. The major dose-limiting toxicity for bleomycin is what?
    Toxicity to the skin and lung
  84. What 4 things can dermal toxicity from bleomycin include?
    Hyperpigmentation, hyperkeratosis, erythema and ulceration
  85. What is the most serious toxicity for bleomycin?
    Pulmonary (particularly fibrosis)
  86. What is the possible mechanism for pulmonary toxicity in
    Increased expression of TGF-β by resident cells
  87. Two derivatives of ______________ show significant
    anti-tumor activity against pediatric leukemias, small cell carcinoma of the
    lung, testicular tumors, Hodgkin’s disease and large cell lymphomas
  88. Epipodophyllotoxins share the same mechanism of action as
    which other types of drugs?
  89. With epipodophyllotoxins, one sees accumulation of cells in
    which of the cell phases?
    S & G2 phases
  90. What are the resistance mechanisms of epipodophyllotoxins?
    • ↑ expression of mdr-1 (P-glycoprotein), Mutation or ↓
    • expression of topo-II and Mutation of p53
  91. The dose-limiting toxicity of epipodophyllotoxins is what?
    Leukopenia (w/less thrombocytopenia)
  92. What are the two common side effects seen with
    GI distress and alopecia
  93. What toxicity is seen with higher doses of
    Hepatic (and hypersensitivity reactions)
  94. What side effect can be seen when using etoposide for small
    cell lung carcinoma and what is it due to?
    Bronchospasm due to additives
  95. Childhood acute lymphoblastic leukemia may develop an acute
    nonlymphocytic leukemia w/ a translocation on chromosome _______ where a gene
    that regulates _______________ ______ _____ ________ (4) found.
    11; pluripotent stem cell proliferation
  96. Teniposide is used to treat refractory _________ in
  97. Is penetration into the CSF great with tenisposide?
  98. What are the major toxicities of teniposide?
    Myelosuppression, n/v
  99. What is the standard agent for treating lymphocytic leukemia?
  100. Some lymphoid malignancies cannot synthesis ____________ for
    protein synthesis.
  101. What does administration of L-asparaginase do?
    • Converts plasma L-asparagine into L-aspartic acid and
    • ammonia depriving cells of substrate.
  102. Resistance of L-asparaginase includes expression of _______
    ___________ in the tumor cells.
    L-asparagine synthetase
  103. How can hypersensitivity reactions be reduced with
    • Use a pegylated enzyme preparation that has 5000 Da
    • monomethyl polyethylene glycol conjugated to the enzyme.
  104. ___________ ________________ can produce a hypersensitivity
    reaction, but not all.
    Neutralizing antibodies
  105. With use of L-Asparaginase, several clotting factors can
    become deficient leading to _________ ________________ (2).
    Spontaneous thrombosis
Card Set
Anti-Neoplastic Agents III
Anti-Neoplastic Agents III