ANTINEOPLASTIC_DRUGS_MS2

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soren101
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ANTINEOPLASTIC_DRUGS_MS2
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2011-09-13 22:43:10
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ANTINEOPLASTIC DRUGS CANCER MS2
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ANTINEOPLASTIC DRUGS CANCER MS2
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  1. EPOETIN ALFA
    MYELOSUPPRESSION

    EPO REPLACEMENT

    IV OR SC

    • Tx
    • --FATIGUE
    • --SOB
  2. DARBEPOETIN
    Tx MYELOSUPPRESSION

    LIKE EPO ALFA BUT LONGER HALF LIFE
  3. OPRELVEKIN
    MYELOSUPPRESSION

    IL-11 = Megakaryocyte growth factor

    • Tx
    • Thrombocytopenia
    • (no platelets) → Hemorrhage
  4. FILGRASTIM
    MYELOSUPPRESSION

    • Granulocyte colony-stimulating
    • factor (G-CSF)

    • Tx
    • Leukopenia

    • i.e. Neutropenia
    • (Neutrophil count < 1000)

    • --infections
    • --fever

    • Rapid recovery (14-21 days)
    • or
    • Delayed recovery (50+ days)

    • *Na dir neutrophils count during a cycle
    • of chemo is the most important value
  5. SARGRAMOSTIM
    MYELOSUPPRESSION

    Granulocyte –Macrophage colony-stimulating factor (GM-CSF)
  6. LEUCOVORIN
    MYELOSUPPRESSION

    FOR BM "RESCUE" for pts taking methotrexate
  7. MECHLORETHAMINE
    ALKYLATING AGENT

    • Polyfunctional alkylating agents: CCNS
    • Nitrogen mustards
  8. PROCARBAZINE
    ALKYLATING AGENT

    OTHER ALKYLATING AGENT: CCNS

    GIVEN PO
  9. CYCLOPHOSPHAMIDE
    ALKYLATING AGENT

    • Polyfunctional alkylating agent: CCNS
    • Nitrogen mustard

    • Given p.o.
    • ---------------------------

    ADVERSE / TOX

    Toxic to urinary bladder

    · Myelosuppression

    · Immunosuppression: used in organ transplant

    · Highly emetic

    • · Acrolein metabolite → non-hemorrhagic & hemorrhagic cystitis → hydration & freq urination nec to prev damage to GU tract.
    • ----Co-admin mesna (Na-2-mercaptoethane sulfate): free-radical scavenger binds acrolein metabolite → prevents GU damage (& rapidly cleared by kidneys)
    • ----“hematuria w/o bacteria”

    SIADH: could cause H2O intox b/c intake incr’d to prev GU damage
  10. NA-2-MERCAPTOETHANE
    SULFATE (MESNA)
    ALKYLATING AGENT

    TO PREVENT GU DAMAGE CAUSED BY CYCLOPHOSPHAMIDE

    • Co-admin mesna (Na-2-mercaptoethane sulfate):
    • --Free-radical scavenger binds acrolein metabolite
    • → prevents GU damage (& rapidly cleared by kidneys)
  11. BUSULFAN
    ALKYLATING AGENT

    Polyfunctional alkylating agent: CCNS

    Given p.o.

    • ADVERSE
    • --PULM FIBROSIS
  12. CARMUSTINE (BCNU)
    ALKYLATING AGENT

    Nitrosureas alkylating agent: CCNS

    Given i.v.

    *Also act in G0 & crosses blood-brain barrier → Tx 1o CNS tumors

    • ADVERSE
    • --PULM FIBROSIS
  13. TEMOZOLAMIDE
    ALKYLATING AGENT

    Other alkylating agent: CCNS

    Given p.o.

    Crosses blood-brain barrier

    Does NOT need bioactivation

    Tx 1o & 2o brain tumors
  14. DACARBAZINE
    ALKYLATING AGENT

    HODGKIN'S DISEASE = B CELL NEOPLASM

    "ABVD"

    • Adriamycin
    • (doxorubicin)

    Bleomycin

    Vinblastine

    Dacarbazine
  15. CISPLATIN
    ALKYLATING AGENT

    Platinum alkylating agents: CCNS

    • Given i.v.
    • --------------------------------------
    • ADVERSE

    Highly emetic → pretreat w/ 5-HT3 blocker + dexomethasone

    • --Nephrotoxicity:
    • ----Pre- & post-treat hydration w/ 0.9% saline → decr toxicity

    ----Carboplatin less renal & GI toxic < cisplatin.

    High frequency hearing loss

    Neurotoxicity = sensory neuropathy
  16. CARBOPLATIN
    ALKYLATING AGENT

    • SAME AS CISPLATIN
    • Platinum alkylating agents: CCNS

    • Given i.v.
    • --------------------------------------

    ADVERSE

    Highly emetic → pretreat w/ 5-HT3 blocker + dexomethasone

    • --Nephrotoxicity:
    • ----Pre- & post-treat hydration w/ 0.9% saline → decr toxicity
    • ----Carboplatin less renal & GI toxic < cisplatin.

    High frequency hearing loss

    Neurotoxicity = sensory neuropathy
  17. METHOTREXATE
    ANTIMETABOLITES

    CCS S-PHASE

    MOA

    Structurally sim to folic acid. Given p.o. or intrathecal.

    • 1. Forms highly-active polyglutamate
    • compounds which persist in cancer cells.

    • 2. Reversibly inhb dihydrofolate
    • (DHF) reductase → prevents synth of tetrahydrofolate (THF)

    3. Lack of THF → decr synth of thymidylate, purine nucleotides & amino acids: Ser & Met.

    • 4. Also inhb several folate-dependent enzs (thymidylate synthetase & glycinamide ribonucleotide formyltransferase (GARFT)) involved in synth of both purines & thymidylate.
    • ---------------------------------------------------
    • ADVERSE

    • 1. Myelosuppression
    • --Bone marrow can be rescued by treatment w/
    • leucovorin (folinic acid)

    2. Nephrotoxicity
  18. 5-FLUOROURACIL
    ANTIMETABOLITES

    CCS S-PHASE

    Pyrimidine (cytosine, uracil & thymine) analog

    *Given i.v., topical for actinic keratoses & basal cell cancers

    1. Metabolite 5-fluoro-2-deoxyuridine 5-phosphate (F-dUMP) irreversibly inhb thymidylate synthetase.

    2. Lack of thymidylate blocks DNA synth: “thymineless death”

    • 3. 5-fluorouridine triphosphate incorp into mRNA → prevents normal tsl of mRNA
    • -------------------------------------------------

    ADVERSE / TOX

    1. Toxic to eyes

    2. Pts w/o enz dihydropyrimidine dehydrogenase (DpD) → cannot inactv 5-FU

    3. Myelosuppression

    4. Stomatitis, mucositis & diarrhea

    5. Hyperpigmentation

    6. Photosensitivity

    7. “Hand-food” syndrome: Painful erythematous desquamation of palms & soles.
  19. CYTARABINE (ARA-C)
    ANTIMETABOLITES

    CCS S-PHASE

    Pyrimidine analog

    Phosphorylated ara-CTP → Inhb DNA polymerase

    • Also phosphorylated ara-CTP incorporated into
    • DNA & RNA

    TOXIC TO CNS
  20. AZACITIDINE
    ANTIMETABOLITES

    CCS S-PHASE

    Pyrimidine analog

    • Inhb enz DNA methyltransferase → turns on tumor
    • suppressor genes.
  21. 6-MERCAPTOPURINE (6-MP)
    ANTIMETABOLITES

    CCS S-PHASE

    • Purine (guanine & adenine) analog
    • 1. Enz hypoxanthine guanine phosphoribosyl transferase (HGPRT) converts 6-MP & 6-TP → Inhb purine synthesis

    • 2. Decr HGPRT actvy → 6-MP & 6-TG resistance
    • ---------------------------------------------
    • ADVERSE / TOX

    • 1. Xanthine oxidase degrades 6-MP.
    • ----Allopurinol (anti-gout drug) inhb xanthing oxidase → incr 6-MP toxicity → Must decr 6-MP dose.
    • ----6-TG not metab by xanth. oxids.

    2. Myelosuppression
  22. BLEOMYCIN
    ANTIBIOTIC DRUG

    CCS G2-PHASE

    Given i.v., i.m., s.c. & intravacavitary (for malignant effusions)

    1. Binds to DNA → forms O2 free radicals → single- & double-stranded breaks.

    2. Block DNA synth

    3. Fragmentation of DNA → Chromosomal abnormalities

    • 4. Cancer cells accumulate in G2
    • -----------------------------------------------
    • ADVERSE / TOX
    • 1. Pulmonary fibrosis*
    • ----Begin w/ dry cough, fine rales & difuse basilar infiltrates on CXR.
    • ----Progresses to pulm. fibrosis.

    2. Lethal anaphylactic rxns, esp w/ lymphoma

    3. Fever & chills w/in 48 hours

    4. Hyperpigmentation of elbows & knees

    5. Hyperkeratosis of palms

    6. No bone marrow depression
  23. DACTINOMYCIN
    ANTIBIOTIC DRUG aka ACTINOMYCIN D

    1. Intercalates into ds-DNA btwn G≡C pairs.

    2. DNA-dependent RNA synth impaired → Block protein synth.

    • 3. (DNA replication is little affected)
    • --------------------------------
    • ADVERSE / TOX

    1. Myelosuppression

    2. Immunosuppression

    3. Radical “recall”: skin inflammation at previously irradiated sites
  24. DOXORUBICIN
    ANTIBIOTIC DRUG aka HYDROXYDUNORUBICIN

    CCNS


    • ·
    • Anthracycline
    • antibiotic drug

    1. Intercalates into DNA → blocks DNA & RNA synth

    2. DNA strand scission (ss- & ds-DNA breaks) via inhbn of Topo II

    3. Alters ion transport through membranes

    4. Generate semiquinone & O2 free radicals

    • 5. Cells die in G2
    • --------------------------------
    • ADVERSE / TOX

    • 1. ♥Heart: Free radicals damage
    • ----Acute: PVCs, transient changes in ST segment & T-wave
    • ----Chronic: cumulative,
    • dose-related cardiomyopathy → ♥ failure
    • ----TOTAL cumulative dose determines likelihood of cardiac damage

    2. Myelosuppression: short duration & rapid recovery

    3. Stomatitis

    4. Radiation recall

    5. Alopecia
  25. ETOPOSIDE
    EPIPODOPHYLLOTOXINS

    CCS LATE S-G2 PHASE

    1. Stabilize bond btwn Topo II & DNA

    2. Inhb Topo II → Double strand breaks remain

    3. DNA degraded

    --Topoisomerases cut ss- or ds-DNA to allow strand(s) to unwind.

    § Breaks are religated after unwinding.

    § Topo I: cuts/religates ss-DNA

    § Topo II: cuts/religates ds-DNA

    • § Topo I & II necess for DNA replication & RNA
    • tsc.

    • --Topo II necess to complete mitosis.
    • ---------------------------------------
    • ADVERSE / TOX

    1. Dose-limiting Myelosuppression

    2. Anaphylaxis

    3. Fever

    4. Hypo-or hypertension

    5. 2* leukemias
  26. TOPOTECAN
    CAMPTOTHECINS

    CCNS

    • Inhb Topo I → DNA damage
    • -------------------------------------
    • ADVERSE / TOX

    1. Myelosuppression

    2. Occasional diarrhea
  27. VINCRISTINE
    &
    VINCBLASTINE
    VINCA ALKALOIDS

    CCS: LATE G2-EARLY-M PHASE

    ON USMLE -- M PHASE

    MOA

    “Spindle poisons”

    • 1. Bind to dimeric tubulin → prevent further
    • polymerization (→ prevent assembly of microtubules)

    2. Already formed microtubules depolymerize.

    • 3. Cells arrest in metaphase b/c mitotic
    • filaments cannot form.

    § Microtubules (heterodimers of α- & β-tuublin) form mitotic spindle.

    § Mitotic spindle separates the duplicate set of chromosomes during cell division.

    • § Microtubules have “dynamic instability” b/c
    • constant remodeling

    • --Remodeling involves constant incorp of free
    • dimmers & simult release of dimmers into solb tubulin pool
    • -----------------------------
    • OTHER INFO

    • Over expression of MDR1 & Pgp170 genes → Incr
    • efflux pumps → cross-resistance btwn different classes of drugs

    • e.g. taxanes (paclitaxel) & vinca alkaloids
    • -------------------------------------
    • ADVERSE / TOX

    VINBLASTINE -- DOSE-LIMITING MYELOSUPPRESSION

    • VINCRISTINE:
    • 1. Dose-limiting Neurotoxicity:
    • o loss of tendon reflexes

    o paresthesias (feet & hands) in a “stocking-glove” distrb (not above knee or elbow)

    o autonomic dysfunction: constipation, orthostatic hypotension

    2. Myelosuppression (less)
  28. PACLITAXEL
    &
    DOCETAXEL
    TAXANES

    CCS - M PHASE

    • MOA
    • “Spindle poisons”

    1. Enhances polymerization of tubulin

    2. Promotes microtubule assembly

    3. Stabilizes microtubules against depolymerization

    4. Prevents “dynamic instability”

    • Causes mitotic arrest b/c anaphase cannot occur.
    • ------------------------
    • OTHER

    • Over expression of MDR1 & Pgp170 genes → Incr
    • efflux pumps → cross-resistance btwn different classes of drugs

    • e.g. taxanes (paclitaxel) & vinca alkaloids
    • ---------------------------------------
    • ADVERSE/TOX

    1. Peripheral neuropathy

    2. Myelosuppression

    3. Myalgias

    • Pretreat w/ corticosteroids → decr severity of other S/E incl:
    • --anaphylaxis,
    • --peripheral edema,
    • --epihora (excessive tearing),
    • --erythematous pruritic maculopapular rash
    • --pathologic nail changes (hypo/hyperpigmentation, oncholysis, Beau-Reil lines)
  29. HYDROXYUREA
    MISCELLANEOUS

    CCS - S PHASE

    • MOA
    • 1. Inhb ribonucleotide reductase

    2. Depletion of deoxynucleoside triphosphate → Prevents DNA synth

    • Treats Sickle-cell disease:
    • --Hydroxyurea turns on fetal Hg (HbF) gene
    • --Adults prod normal HbF → fetal Hb in RBCs
    • prevents sickling
    • ----------------------------------
    • TOX
    • -MYELOSUPPRESSION
  30. L-ASPARAGINASE
    MISCELLANEOUS

    • MOA
    • --Hydrolyzes serum asparagine (essential amino
    • acid for leukemia cells).
    • --Normal cells can synth L-Asn.
    • ----------------------------

    • TOX
    • Hepatotoxicity
  31. IMATINIB
    MISCELLANEOUS

    • MOA
    • Blocks binding of ATP to Bcr-Abl tyrosine kinase → Inhb phosphorylation of kinase substrate (inhb oncogene product)

    Philidelphia (Ph) chromosome w/ t(9:22) → codes for fusion oncoprotein Bcr-Abl, a tyrosine kinase which is essential for prolif/survival of abnorm WBCs → chronic myelocytic (myelogenous) leukemia.
  32. BORTEZOMIB
    MISCELLANEOUS

    MOA

    1. Inhb actvy of 26S proteasome

    2. Prevents degradation of IκB (inhibitor)

    3. Enhances apoptosis by preventing action of NF-κB (nuclear factor kappa: upreg DNA tsc, cell survival, inhb apoptosis)

    Treats multiple myeloma (plasma cell cancers).
  33. RITUXIMAB
    MONOCLONAL ANTIBODIES

    • MOA
    • Binds CD20 Ag expressed on all malignant B cell lymphocytes
  34. TRASTUZUMAB
    MONOCLONAL ANTIBODIES

    • MOA
    • · Blocks EGFR coded by HER2/neu (ErbB-2) gene

    • Treats breast cancer tumors (+) for HER2/neu
    • ----------------------------------

    ADVERSE TOX

    CARDIAC DYSFUNC, ESP IF Tx w DOXORUBICIN
  35. CETUXIMAB
    MONOCLONAL ANTIBODIES

    • MOA
    • · Blocks EGFR (HER1 EGFR) in colorectal cancer (60-75% pts express)

    Block cell prolif, survival & angiogenesis
  36. CELL CYCLE
    • G0
    • Differentiation. Resting phase.

    • G1 Synthesis of compounds needed to synthesize
    • DNA (18-30 hours)

    S DNA replication & repair. Chromosomes double (16-20 hours)

    • G2 Synthesis of molecules needed for mitosis
    • (2-10 hours)

    M Mitosis (0.5-1 hour)
  37. HEAT TOXICITY
    Anthracyclines = doxorubicin
  38. LUNG TOXICITY
    BLEOMYCIN
  39. KIDNEY TOX
    CISPLATIN
  40. URINARY BLADDER TOX
    CYCLOPHOSPHAMIDE
  41. CNS TOC
    CYTARABINE
  42. PNS TOX
    --Vincristine

    --Paclitaxel
  43. · EYE TOX
    5-FU
  44. LIVER TOX
    Asparaginase
  45. DERM TOX
    (skin/nails)
    Capecitabine
  46. COMBO THERAPY FOR HODGKIN'S
    B-CELL NEOPLASM

    "MOPP"

    Mechlorethamine

    Oncovin (vincristine)

    Procarbazine

    Prednisone

    • -------------------------
    • Also ABVD:

    • Adriamycin
    • (doxorubicin)

    Bleomycin

    Vinblastine

    Dacarbazine
  47. COMBO THERAPY FOR NON-HODGKIN'S LYMPHOMA
    "CHOP"

    Cyclophosphamide

    • Hydroxydaunorubicin
    • (doxorubicin)

    • Oncovin
    • (vincristine

    Prednisone
  48. COMBINATION THERAPY FOR BREAST CANCER
    "CMF"

    Cyclophosphamide

    Methotrexate

    • 5-FU
    • -----------------------------

    Also CAF:

    Cyclophosphamide

    • Adriamycin
    • (doxorubicin)

    5-FU
  49. Polyfunctional alkylating agents: Cell Cycle Non-Specific (CCNS). CONCENTRATION-dependent
    1) Mechlorethamine

    2) Thiotepa

    3) Cyclophosphamide

    4) Melphalan

    5) Chlorambucil

    6) Busulfan
  50. Nitrosoureas alkylating agents: Cell Cycle Non-Specific (CCNS)
    Carmustine (BCNU)

    Lomustine (CCNU)

    Also act in G0 → Tx 1o tumors of CNS
  51. PLATINUM ALKYLATING AGENTS: Cell Cycle Non-Specific (CCNS)
    Cisplastin

    Carboplatin
  52. OTHER ALKYLATING AGENTS: CCNS
    Procarbazine

    Temozolamide
  53. Anthracycline antibiotic drugs: CCNS
    Doxorubicin aka Hydroxydaunorubicin

    Idarubicin
  54. ANTIBIOTIC DRUGS: CCNS
    Dactinomycin (Actinomycin D)

    Mitomycin C
  55. CAMPTOTHECINS: CCNS
    Topotecan

    Irontecan
  56. GLUCOCORTICOIDS: CCNS
    PREDNISONE
  57. CCNS
    CELL CYCLE NON-SPECIFIC

    1) Can work at any step in the cell cycle, including G0

    2) Cells are more sensitive in late G1 & S phases b/c polynucleotides are more susceptible to alkylation in the unpaired state than in the helical form.

    • 3) Toxicity ~ expressed when cells enter S phase → Block progression through
    • cell cycle.


    e.g. doxorubicin: intercalates into DNA → DNA strand scission (single & double strand breaks) via inhibition of topoisomerase II, (cells die in G2)
  58. G0-PHASE: CCS DRUGS
    • Corticosteroids suppress mitosis & cause
    • apoptosis of non-dividing cells

    G0 = 40% CELL CYCLE
  59. S-PHASE: CCS DRUGS
    Antimetabolites:

    • 1) 5-fluorouracil (5-FU)
    • 2) 6-mercaptopurine (6-MP)
    • 3) Methotrexate
    • 4) Gemcitabine
    • 5) Capecitabine
    • 6) Cytarabine
    • 7) Hydroxyurea

    S-PHASE = 40% CELL CYCLE
  60. G2-PHASE: CCS DRUGS
    • 1. Bleomycin
    • 2. Etoposide
    • 3. Teniposide

    G2-PHASE = 18% CELL CYCLE
  61. LATE G2 / EARLY M-PHASE: CCS DRUGS
    1. Vincristine

    2. Vinblastine
  62. M-PHASE: CCS DRUGS
    • 1. Paclitaxel
    • 2. Docetaxel
    • 3. Vincristine
    • 4. Vinblastine

    2% OF CELL CYCLE
  63. CCS: CELL CYCLE SPECIFIC DRUGS
    1. Inhb cell division by acting during a specificcell cycle phase. Cells in sensitive phase are killed.

    2. CCS drugs most effective in hematologic cancers & tumors w/ a relatively large # of cells in the “growth fraction.”
  64. ALKYLATING AGENTS MOA
    • 1. Damage DNA via cross-linking (bifunctional
    • drugs w/ 2 reactive groups)
    • --OR--
    • 2. Damage DNA via single-strand breaks (monofunctional drugs w/ 1 reactive group)

    Primary site of DNA alkylation is N7 position of Guanine. O6 also attacked.

    • Alkylation of DNA:
    • 1. Inhb synthesis of DNA, RNA & proteins

    • 2. Causes misreading of DNA
    • ------------------------------------------

    ADVERSE / TOX

    • 1. Myelosuppression & immunosuppression →
    • dose-limiting toxicity

    2. n/v w/in 30-60 min of Tx. Must pretreat w/ 5-HT3 blockers (e.g. ondasteron)

    3. Teratogenic & carcinogenic (2^ leukemias): Most common cancer caused by chemo (2^ cancer) is Acute Myelogenous Leukemia (AML)

    • 4. Pulmonary fibrosis (rare)
    • -- Bulsulfan
    • -- Chlorambucil
    • -- Melphalan
    • -- Nitrosureas

    5. Amenorrhea & azoospermia

    • 6. Hepatic venooculsive disease (HVOD or VOD): chemo obliterates branches of the small hepatic
    • veins. Can → portal hypertension.
  65. ALKYLATING AGENTS ADVERSE / TOX
    ADVERSE / TOX

    • 1. Myelosuppression & immunosuppression →
    • dose-limiting toxicity

    2. n/v w/in 30-60 min of Tx. Must pretreat w/ 5-HT3 blockers (e.g. ondasteron)

    • 3. Teratogenic & carcinogenic (2^ leukemias): Most common cancer
    • caused by chemo (2^ cancer) is Acute Myelogenous Leukemia (AML)

    • 4. Pulmonary fibrosis (rare)
    • -- Bulsulfan
    • -- Chlorambucil
    • -- Melphalan
    • -- Nitrosureas

    5. Amenorrhea & azoospermia

    • 6. Hepatic venooculsive disease (HVOD or VOD): chemo obliterates branches of the small hepatic
    • veins. Can → portal hypertension.

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