Miscellaneous Drugs

  1. What is the Log-Kill Hypothesis?
    • Cytotoxic actions follow 1st order kinetics: kill a fixed percentage of tumour cells, not a fixed number
    • One rationale for durg combination
  2. Growth Fraction
    • The # of actively dividing cells
    • Nl cells that have high growth fraction: bone marrow, GI lining, etc. have higher sensitivity to anticancer drugs
  3. Cell Cycle Specificity:
    • Cell Cycle Specific: are more sensitive on cells that are in a specific phase of cell cycle, and are more effective in tumours with high-growth fractions (ie leukemia, lymphomas)
    • Cell Cycle Nonspecific: bind to and damage DNA, can be used in low or high growth fraction tumours
  4. Anticancer Drugs: Antimetabolites
    • all S phase specific
    • Methotrexate
    • 5-FU
    • 6-MP
    • 6-TG
    • Cytarabine
  5. Anticancer Drug: Antimetabolite: Methtrexate
    • Mechanism: folic acid analgue that inhibits THF reductase = decreased dTMP = decreased DNA & protein synthesis, in S phase of cell cycle
    • Clinical use:
    • Cancers: Leukemia, lymphomas, choriocarcinomas, sarcomas
    • Nonneoplastic: abortion, ectopic pregnancy, RA, psoriasis
    • Toxicity: myelosuppression (reversible with Leucorvorin - a folinic acid), macrovesicular fatty chg in liver; mucositis, teratogenic
  6. Anticancer Drug: Antimetabolite: 5-Fluorouracil (5-FU)
    • Mechanism: Pyrimidine analogue deactivated to 5-F DUMP = covalently complexes folic acid, this complex = inhibits thymidilate synthase = decreased dTMP = decreased DNA/protein synthesis (s phase)
    • Clinical use: coon cancer, other solid tumours, basal cell carcinoma (topical), synergy with MTX
    • Toxicity: myelosuppression, which is NOT reversible with leucovroin, OD = can rescue with thymidine, photosensitivity
  7. Anticancer Drug: Antimetabolite: 6-Mercaptopurine
    • Mechanism: purine (thiol) analogue = decreases de novo purine synthesis, activated by HGPRTase
    • Clinical use: leukemia, lymphoma (not CLL or Hodgkins)
    • Toxicity: bone marrow, GI, liver, metaboized by xanthine oxidase = increases toxicity with allopurinol
  8. Anticancer Drug: Antimetabolite: 6-thioguanine
    • Mechanism; purine (thiol) analoque = decreases de novo purine synthesis, activated by HGPRTase
    • Clinical use: acute lymphoid leukemia
    • Toxicity: bone marrow depression, liver, can be given with allopurinol
  9. Anticancer Drug: Antimetabolite: Cytarabine (ara-C)
    • Mechanism: pyrimidine antagonist = inhibtion of DNA polymerase
    • Clinical use: AML, ALL, high grade non-Hodgkin's lymphoma
    • Toxicity: leukopenia, thrombocytopenia, megaloblastic anemia
  10. Anticancer Drug: Antitumour Abx:
    • Dactinomycine
    • Doxorubicin
    • Bleomycin
    • Etoposide (VP-16) teniposide
  11. Anticancer Drug: Dactinomycin (ACTinomycin D)
    • Mechanism: intercalates in DNA
    • Clinical use: Wilm's tumour, Ewing's sarcoma, rhabdomyosarcoma, used in childhood cancers (children often ACT out)
    • Toxicity: myelosuppression
  12. Anticancer Drug: Doxorubicin (Adriamycine, daunorubicin)
    • Mechanism: generate free radicals, noncovalently interaclate in DNA = breaks in DNA= decreases replication
    • Clinical use: part of the ABVD combo regimin for Hodgkins, also for myelomas, sarcomas, solid tumours (breast, ovary, lung)
    • Toxicity: cardiotoxicity, myelosuppression, marked alopecia, toxic to extravasation tissues
  13. Anticancer Drugs: Bleomycin
    • Mechanism: G2-phase specific, induces formation of free radications = DNA strand breaks
    • Clinical use: testicular cancer, Hodgkins lymphoma part of the (ABVD combo)
    • Toxicity: pulmonary fibrosis, skin chgs, minimal myelosuppression
  14. Anticancer Drugs: Etoposide (VP-16), teniposide
    • Mechanism: late S- to G2- phase specific, inhibits TOPII = Increases DNA degeneration
    • Clinical use: small cell carcinoma of lung, prostate, testicular carcinoma
    • Toxicity: myelosuppression, GI irritation, alopecia
  15. Anticancer Drugs: Alkylating Agents
    • Cyclophosphamide, isofamide
    • Nitrosoureas
    • Busulfan
  16. Anticancer Drugs: Cyclophosphamide
    • Mechanism: covalently X-link (interstrand) DNA at guanine N-7, require bioactivation in the liver
    • Clinical use: non-hodgkins lymphoma, breast & ovarian carcinomas, immunosuppressants
    • Toxicity: myelosuppression, hemorrhage cystitis, partially prevented by mesna
  17. Anticancer Drugs: Nitrosoureas (carmustine, lomustine, semustine, streptozosin)
    • Mechanism: requires bioactivation, crosses BBB = CNS action
    • Clinical use: brain tumours (including glioblastoma multiformes)
    • Toxicity: CNS toxicity (dizziness, ataxia)
  18. Anticancer Drugs: Busulfan
    • Mechanism: alkylates DNA
    • Clinical use: CML, also for ablating bone marrow in hematopoietic stem cell transplants
    • Toxicity: pulmonary fibrosis and hyperpigmentation
  19. Anticancer Drugs: Microtubule Inhibitors
    • Vincristine, vinblastine
    • PacliTAXel, other TAXols
  20. Anticancer Drugs: Vincristine, Vinblastine
    • Mechanism: alkaloids that bind to tubulin in M phase and block polymerization of microtubules tso that mitotic spindles cannot stay together
    • microtubules are the vines in your cells
    • Clinical use: part of the MOPP (Oncovin = vincristine) regimen for Hodgkin's lymhoma, Wilm's tumour, choriocarcinoma
    • Toxicity: Vincristine - neurotoxicity (areflexia, peripheral neuritis), paralytic ileus. VinBLASTine BLASTs Bone marrow = causing bone marrow suppression
  21. Anticancer Drugs: Paclitaxel, and other taxols
    • Mechanism: Hyperstabilize the polymerized microtubules in M phase so that the mitotic spindle cannot breakd own (anaphase cannot occur) it is TAXing to stay polymerized
    • Clinical use: ovarian and breast carcinomas
    • Toxicity: myelosuppression and hypersenstivity
  22. Antcancer Drugs: Cisplatin, carboplatin
    • Mechanism: cross-link DNA
    • Clinical use: testicular, bladder, ovary and lung carcinomas
    • Toxicity: nephrotoxicity, acoustic nerve damage
  23. Anticancer Drugs: Hydroxyurea
    • Mechanism: inhibitis Ribonucleotide Reductase = decreased DNA synthesis (S-phase specific)
    • Clinical use: melanoma, CML, sickle cell disease (increases HbF)
    • Toxocity: bone marrow suppression, GI upset
  24. Anticancer Drugs: Prednisone
    • Mechanism: may trigger apoptosis, may even work on non-dividing cells
    • Clinical use: mostly used in glucocorticoid in cancer them, CLL, Hodgkin's lymphoma (part of MOPP regimine), also an immunosuppressive in autoimmune diseases
    • Toxicity: Cushing-like syndrome, immunosuppression, cataracts, acne, osteoporosis, htn, peptic ulcers, hyperglycemia, psychosis
  25. Anticancer Drugs: Tamoxifen, raloxifene(SERMs)
    • Mechanism:SERMs: receptor antagonist in breast, agonists in bone, block the binding of estrogen to estrogen receptor +ve cells
    • Clinical use: breast cancer, prophylaxis of osteoporosis
    • Toxicity: endometrial carcinoma via partial agonist effects: "hot flashes", Raloxifene does not cause endometrial carcinoma bc it is an endometrial agonist
  26. Anticancer Drugs: Herceptin
    • Mechansim: monoclonal antibody against HER-2 (erb-2B), helps kill breast cener cells that overexpress HER-2, possibly thru antibody-dependent cytotoxicity
    • Clinical use: met breast cancer
    • Toxicity: cardiotoxic
  27. Anticancer Drugs Imatinib (Gleevac)
    • Mechanism: philadelphia chs bcr-abl tyrosine kinase inhibitor
    • Clinical use: CML, GI stromal cells
    • Toxicity: fluid retention
Card Set
Miscellaneous Drugs
Anticancer Drugs