Oncology Exam #2

  1. Homoharringtonine Source:
    • Plant-derived alkaloid indigenous to: Eastern Asia/China, Japan, and India
    • The bark of Cephalotaxus harringtonia var. drupacea (Sieb & Zucc.)
    • Natural homoharringtonine is extracted from the bark of Cephalotaxus sp.
    • Semi-synthetic homoharringtonine is known as Omacetaxine Mepesuccinate
    • Common names include: Plum Yew, Japanese Plum Yew, Harrington Plum Yew, and Cow Tail Pine
  2. Homoharringtonine chemistry:
    • Tertiary amine
    • Cephalotaxine derivative in which the secondary alcohol group has been esterified with different naturally occurringacids
    • Homoharringtonine is a homologue (one additional methylene function in esterchain) of harringtonine
  3. Omacetaxine Mepesuccinate (Homoharringtonine) MOA:
    • Induces apoptosis (programmed celldeath) in myeloid cells via inhibition of protein synthesis
    • Inhibits angiogenesis
    • Occurs as a result of reversible inhibition of ribosome/elongation factor complex
    • Acts independently of tyrosine kinase inhibitors
  4. Omacetaxine Mepesuccinate (Homoharringtonine) Applications:
    Potentially in CML, AML and MDS (myelodysplastic syndrome [increased risk to transformation to AML]

    Phase 3 studies in CML
  5. Omacetaxine Mepesuccinate (Homoharringtonine) special AEs:
    Nonhematologic toxicities were infrequently observed
  6. Eribulin Source:
    Synthetic macrocyclic ketone analog of halichondrin B, a large macrocyclic polyether first isolated from the sponge Halichondria okadai in 1986

    **Halichondrin B was highly cytotoxic in murine leukemia cells**
  7. Eribulin Chemistry:
    • Macrocyclic polyether
    • Consists of “right-hand portion” of Halichondrin B structure
    • Acetate, malonate, methylmalonate metabolites
  8. Eribulin MOA:
    • Tubulin depolymerizer
    • Disrupts polymerization of themicrotubules necessary in mitosis
    • Binds near the Vinca domain
  9. Eribulin Applications:
    Advanced, “heavily-treated”, metastatic breast carcinoma

    November 15, 2010 – FDA approves for thetreatment of patients with metastaticbreast cancer who have received at leasttwo prior chemotherapy regimens for latestagedisease
  10. Major Biosynthetic Precursor of Eribulin:
  11. Bleomycin Source:
    Mixture of cytotoxic glycopeptide antibiotics isolated as their water soluble sulfate salts from cultures of a strain of Streptomyces verticillus
  12. Bleomycin Chemistry:
    • Isolated as a blue-colored Cu(II) coordinated complex
    • The Cu+2 is removed prior to marketing via catalytic reduction
    • Increases cost but frees up critical functional groups for chelation with intracellular Fe+2
    • Bleomycin complexes (chelates) in vitro with divalent and trivalent cations
  13. Bleomycin MOA:
    • Contains an iron-binding region and aDNA-binding region at opposite ends of the molecule
    • Iron is a mandatory co-factor for free radical generation and resulting cytotoxicity of bleomycin
    • Cytotoxicity results from activated oxygenfree radical species which produce single- and double-strand DNA breaks
  14. Bleomycin Applications:
    • Hodgkin’s and Non-Hodgkin’s lymphomas
    • Germ cell tumors
    • Head and neck squamous cell carcinoma
    • Skin, cervix, vulvar squamous cell carcinoma
  15. Bleomycin special AEs:
    • Pulmonary Toxicity (most severe toxicity): Pneumonitis & Pulmonary Fibrosis
    • Dermatologic Rxns: desquamation, rash, hyperpigmentation, hyperkeratosis
  16. Dactinomycin Source:
    Major antibiotic of a mixture ofactinomycins produced by strains of Streptomyces parvulus
  17. Dactinomycin Chemistry:
    • Heteroaromatic chromopeptide
    • Planar phenoxazone chromophore
  18. Dactinomycin MOA:
    • Preferentially binds to guanine-cytosinebase pairs
    • Binds to single- & double-stranded DNA as an intercalator with formation of toxic oxygen free radicals that promote strand breaks
  19. Dactinomycin Common Applications:
    • Wilms’ tumor
    • Rhabdomyosarcoma
    • Choriocarcinoma
    • Ewing’s sarcoma
  20. Dactinomycin Special AEs:
    • Dermatological: hyperpigmentation & extravasation
    • Red-orange color of bodily fluids
  21. Romidepsin Source:
    First isolated from cultures of Chromobacterium violaceum by Fujisawa Pharm. in 1990
  22. Romidepsin Chemistry:
    • Depsipeptide: A peptide having both amide and ester bonds
    • Bicyclic peptide consisting of 4 amino acid residues and a novel acid
  23. Romidepsin MOA:
    Histone deacetylase inhibitor (HDI)

    HDIs possess anti-tumor activity: Regulate gene transcription or translation; Induce cell cycle arrest and apoptosis through histone hyperacetylation
  24. Romidepsin Common Applications:
    • Cutaneous T-cell Lymphoma (CTCL)
    • Peripheral T-cell Lymphoma (CTCL)
  25. Romidepsin Special AEs:
    • Asthenia (weakness)
    • ECG changes -- requires periodic monitoring of ECG and serum electrolytes
  26. Mitomycin Source:
    One member of a group of antitumor antibiotics isolated from cultures of Streptomyces caespitosus
  27. Mitomycin Chemistry:
    • Mitosanes (1,2-disubstituted indoloquinones)
    • Pyrrolo [1,2-a] indole nucleus
    • Contains quinone, aziridine, and carbamate functions
    • Only compound in nature to contain an aziridine ring
    • Water soluble, Blue-violet colored solution
    • Unstable in both acidic and alkaline media
    • Limited stability of reconstituted solutions
  28. Mitomycin MOA:
  29. Mitomycin Common Applications:
    • Disseminated adenocarcinoma of the stomach and pancreas
    • Unlabeled used: Superficial bladder cancer; Adjunct to surgical excision in primary or recurrent pterygia (web-like superficial growth on the subconjunctiva)
  30. Mitomycin special AEs:
    • Dose-related Hemolytic-uremic syndrome
    • Dermatologic Rxns
    • Interstitial pneumonitis
  31. Apaziquone Source/Chemistry:
    • Synthetic indoloquinone
    • Analog of mitomycin C
  32. Major Biosynthetic Precursor of Apaziquone:
    Mitomycin C
  33. Apaziquone MOA:
    • Bioreductive prodrug
    • Intracellular reductases catalyze the conversion to active metabolites in hypoxic cells
    • Active metabolites alkylate DNA producing apoptotic cell death
  34. Apaziquone Common Applications:
    Therapy of non-muscle invasive (superficial) bladder cancer via intravesical instillation following transurethral resection (TUR) of bladder tumor
  35. Streptozocin Source:
    Fermentation product of Streptomyces achromogenes
  36. Streptozocin Chemistry:
    • Pale gold water soluble nitrosourea
    • 2-Deoxy-2-(3-methyl-3-nitrosoureido)-Dglucopyranose
    • Mixture of alpha and beta anomers, with solutions undergoing mutarotation
  37. Streptozocin MOA:
    Decomposes to form carbonium ions that are electrophilic and can alkylate or carbamoylate various purines or pyrimadines to form adducts involved in inter- or intrastrand DNA cross-linking

    Also, methylates guanine at the O-6 position and irreversibly inactivates DNA-repair enzyme, mammalian alkyl transferase
  38. Streptozocin Common Applications:
    Metastatic islet pancreatic carcinoma
  39. Streptozocin Special AEs:
    • Very severe nausea and vomiting
    • Nephrotoxicity
    • Myelotoxicity is rare
  40. Doxorubicin Source:
    First isolated from cultures of Streptomyces peucetius var. caesius
  41. Doxorubicin Chemistry:
    • Cytotoxic glycosidic anthracycline
    • Part of the rhodomycin group of compounds
    • Today is prepared via semi-synthesis from daunorubicin
    • Planar anthraquinone nucleus linked glycosidically to an aminosugar (daunosamine)
  42. This compound is a major biosynthetic precursor of Daunorubicin
  43. Doxorubicin MOA:
    • Intercalates between base pairs in DNA double helix, affecting DNA and RNA synthesis
    • Generates reactive oxygen intermediates and free radicals
    • Inhibits Topoisomerase-II
  44. Doxorubicin Common Applications:

    • Acute lymphoblastic leukemia (ALL)
    • Hodgkin’s and non-Hodgkin’s lymphomas
    • Carcinomas: Breast, Ovarian, Bladder
    • Sarcomas: Kaposi’s sarcoma (AIDS-related)
  45. Doxorubicin Special AEs:
    • Cardiovascular (both acute and chronic): Arrhythmias & CHF
    • Discoloration of body fluids: Urine turns Red-to-orange
    • Strong vesicant
  46. Dexrazoxane Chemistry:
    • S-(+)- isomer of razoxane
    • A diamine and a di-imide
    • A cyclic derivative of EDTA
  47. Dexrazoxane MOA:
    A cardioprotective intracellular chelating agent that reduces (or prevents) the incidence and severity of cardiotoxicity associated with anthracycline-derived antitumor agents
  48. Epirubicin Source:
    • Semisynthetic analog of doxorubicin
    • Water soluble HCl salt is employed
  49. Epirubicin Chemistry:
    • C-4’ epimer of doxorubicin
    • Same physical/chemical properties as doxorubicin
    • Red-orange color
  50. Epirubicin MOA:
    Same as Doxorubicin: inhibits topoisomerase-II
  51. Epirubicin Common Applications:
    • Adjuvant for early stage breast cancer that has spread to the regional (axillary) lymph nodes but has been treated surgically with removal of all known tumor
    • Metastatic breast carcinoma
    • Gastric carcinoma
  52. Epirubicin Special AEs:
    Same as Doxorubicin (cardiotoxicity & discoloration of bodily fluids) with slightly less cardiotoxicity
  53. Daunorubicin Source:
    • Originally isolated from cultures of Streptomyces peucetius var. caesius
    • Also obtained from cultures of Streptomyces coeruleorubidus
  54. Daunorubicin Chemistry:
    • A C-8 deoxy-doxorubicin derivative
    • Same physical and chemical properties as doxorubicin
    • Red-orange color
    • Water soluble HCl salt used
  55. Daunorubicin MOA:
    same as doxorubicin: inhibits Topoisomerase-II
  56. Daunorubicin Common Applications:
    • Acute leukemias (lymphoblastic andmyelogenous)
    • Kaposi’s Sarcoma (AIDS-related)
  57. Daunorubicin Special Adverse Effects:
    Same as Doxorubicin: Cardiotoxicity and bodily-fluid discoloration
  58. Idarubicin Source:
    • Synthetic analog of daunorubicin
    • 1-Demethoxydaunorubicin ---- Demethoxylation flattens the aromatic ring facilitating intercalation between base pairs
    • High degree of lipophilicity affords increased rate of cellular uptake
    • Same phys/chem properties as doxorubicin
  59. Idarubicin MOA:
    • Same as doxorubicin: inhibits topoisomerase-II
    • Partially overcomes MDR
  60. Idarubicin Common Applications:
    • Acute leukemias (AML, ALL)
    • Chronic leukemia (CML) in blast crisis
  61. Idarubicin Special AEs:
    Same as Doxorubicin: cardiotoxicity and bodily-fluid discoloration
  62. Valrubicin Source/Chemistry:
    • Semisynthetic analog of doxorubicin
    • Valeric acid ester of the N-trifluoroacetylamide of doxorubicin ---- Basic amine nitrogen of doxorubicin is lost, and replaced with neutral amidic nitrogen; Water solubility is low
    • High degree of lipophilicity affords increased rate of cellular uptake
    • Supplied in Cremophor EL/Dehydrated Alcohol mixture as a solution
  63. Valrubicin MOA:
    Same as Doxorubicin: inhibits topoisomerase II (but is less bound to DNA)
  64. Valrubicin Common Applications:
    Intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients who would be poor candidates for immediate cystectomy
  65. Valrubicin Special AEs:
    • Local reactions: Irritation, Urgency, Frequency, Dysuria
    • Systemic reactions are uncommon as total recovery of voided anthracyclines is 99%,with systemic exposure being negligible
  66. Sabarubicin Chemistry:
    A C-1 demethoxy-doxorubicin disaccharide
  67. Sabarubicin MOA:
    • Same as Doxorubicin: More marked topoisomerase II mediated cleavage
    • Significant activity against a number of tumors
  68. Mitoxantrone Source:
    an analog of ametantrone
  69. Mitoxantrone Chemistry:
    • A dihydroxyametantrone
    • Blue-black solid
    • Forms water soluble HCl salt
    • Not glycosylated (as doxorubicin family)
    • Amphoteric
  70. Mitoxantrone MOA:
    Same as Doxorubicin: inhibits Topoisomerase II
  71. Mitoxantrone Common Applications:
    • Acute myelogenous leukemia (AML)
    • Advanced hormone-refractory prostatecancer
    • Non-Hodgkin’s lymphoma
    • Reduction of neurologic disability orfrequency of relapses in multiple sclerosis(MS) patients (uncommon application)
  72. Mitoxantrone Special AEs:
    Same as Doxorubicin: Cardiotoxicity (CHF)
  73. Pixantrone Source:
    • A synthetic aza-anthracenedione
    • Discovered in a search for novel heteroanalogs of anthracenediones
  74. Pixantrone Chemistry:
    • Blue solid
    • Forms water soluble HCl salt
    • Pixantrone = pyridine
    • Not glycosylated (as doxorubicin family)
  75. Pixantrone MOA:
    A novel major groove binder
  76. Pixantrone Common Applications:
    Relapsed or refractory Non-Hodgkins lymphoma
  77. Pixantrone Special AEs:
    • Incidence of severe adverse effects was similar between the drug and the control arm
Card Set
Oncology Exam #2
Schiff & Gold Material