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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
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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
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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
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Anticancer Drugs: Antimetabolites
- all S phase specific
- Methotrexate
- 5-FU
- 6-MP
- 6-TG
- Cytarabine
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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
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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
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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
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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
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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
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Anticancer Drug: Antitumour Abx:
- Dactinomycine
- Doxorubicin
- Bleomycin
- Etoposide (VP-16) teniposide
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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)
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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
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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
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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
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Anticancer Drugs: Alkylating Agents
- Cyclophosphamide, isofamide
- Nitrosoureas
- Busulfan
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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
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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)
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Anticancer Drugs: Busulfan
- Mechanism: alkylates DNA
- Clinical use: CML, also for ablating bone marrow in hematopoietic stem cell transplants
- Toxicity: pulmonary fibrosis and hyperpigmentation
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Anticancer Drugs: Microtubule Inhibitors
- Vincristine, vinblastine
- PacliTAXel, other TAXols
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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
- Toxicity: Vincristine - neurotoxicity (areflexia, peripheral neuritis), paralytic ileus. VinBLASTine BLASTs Bone marrow = causing bone marrow suppression
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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
- Toxicity: myelosuppression and hypersenstivity
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Antcancer Drugs: Cisplatin, carboplatin
- Mechanism: cross-link DNA
- Clinical use: testicular, bladder, ovary and lung carcinomas
- Toxicity: nephrotoxicity, acoustic nerve damage
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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
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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
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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
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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
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Anticancer Drugs Imatinib (Gleevac)
- Mechanism: philadelphia chs bcr-abl tyrosine kinase inhibitor
- Clinical use: CML, GI stromal cells
- Toxicity: fluid retention
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