Anti Cancer New Program

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  • 1. ANTI ~ CANCER DRUGS Zenaida N. Maglaya, MD, FPSECP
  • 2. CANCER
    • is a disease in which there in uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells.
  • 3. Special Characteristics of Cancer Cells
    • Uncontrolled Proliferation
    • Dedifferentiation and loss of function
    • Invasiveness
    • Metastasis
  • 4. Management of Cancer
    • Surgical
    • Irradiation
    • Chemotherapy
  • 5. PHASES OF CELL CYCLE
  • 6. Mitosis M Synthetic S Pre-Synthetic G 1 Post –Synthetic G 2 DIFFEREN-TIATION G 0
  • 7. Cell Cycle Non – Specific (CCNS) Agents
    • ALKYLATING
    • AGENTS
    • Busulfan
    • Carmustine
    • Cyclophosphamide
    • Lomustine
    • Mechlorethamine
    • Melphalan
    • Thiothepa
    • ANTHRACYCLINES
    • Daunorubicin
    • Doxorubicin
    • Epirubicin
    • Idarubicin
    • Mitoxantrone
    • ANTI TUMOR
    • ANTIBIOTICS
    • Dactinomycin
    • Mitomycin
    • CAMPTOTHECINS
    • Irinotecan
    • Topotecan
    • PLATINUM ANALOGS
    • Carboplatin
    • Cisplatin
    • Oxaliplatin
  • 8. Cell Cycle Specific (CCS) Agents
    • ANTIMETABOLITES
    • Capecitabine
    • Cladribine
    • Cytarabine
    • Fluorouracil
    • Gemcitabine
    • Mercaptopurine
    • Methotrexate
    • Thioguanine
    • ANTITUMOR ANTIBIOTIC
    • Bleomycin
    • EPIPODOPHYLLO-
    • TOXINS
    • Etoposide
    • Teniposide
    • TAXANES
    • Docetaxel
    • Paclitaxel
    • VINCA ALKALOIDS
    • Vinblastine
    • Vincristine
    • Vinorelbine
  • 9.
    • CCS:
    • Hematological malignancies,
    • solid tumors in growth fraction
    • CCNS:
    • low groth fraction solid tumors
    • high growth fraction tumors
  • 10. CANCER CHEMOTHERAPEUTIC AGENTS
    • C. CYTOTOXIC ANTIBIOTICS
    • microbial in origin
    • prevent cell division
    • D. PLANT DERIVATIVES
    • affect microtubules and formation of mitotic spindle
  • 11.  
  • 12.  
  • 13. CANCER CHEMOTHERAPEUTIC AGENTS
    • II. HORMONES
    • suppress hormone secretion
    • antagonize hormone action
    • III. MISCELLANEOUS AGENTS
  • 14. CLASSIFICATION OF ANTI-CANCER DRUGS
  • 15. POLYFUNCTIONAL ALKYLATING AGENTS
    • A. NITROGEN MUSTARD
    • 1. CYCLOPHOPHAMIDE
    • 2. CHLORAMBUCIL
    • 3. MECHLORETHAMINE
    • 4. IFOSFAMIDE
    • 5. MELPHALAN
    • 6. ESTRAMUSTINE
    • B. NITROSOUREA
    • CARMUSTINE(BNCU)
    • 2. SEMUSTINE (methyl CCNU)
    • 3.LOMUSTINE( CCNU)
    • 4.STREPTOZOCIN
  • 16. POLYFUNCTIONAL ALKYLATING AGENTS
    • C.ALKYL SULFONATE
    • 1. BUSULFAN
    • D.AZIRIDINE
    • 1. THIOTEPA
    • E. TREOSULPHAN
  • 17. RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS
    • PROCARBAZINE
    • CISPLATIN
    • DACARBAZINE
    • CARBOPLATIN
    • ALTRETAMINE
  • 18. ANTIMETABOLITES
    • A. FOLATE ANTAGONIST
    • 1. METHOTREXATE
    • B. PURINE ANTAGONIST
    • 1. MERCAPTOPURINE 4. FLUDARABINE
    • 2. THIOGUANINE 5. PENTOSTATIN
    • 3. CLADRIBINE
    • C. PYRIMIDINE ANTAGONIST
    • 1. FLUOROURACIL 3. CYTARABINE
    • 2. CAPECITABINE 4. GEMCITABINE
  • 19. PLANT ALKALOIDS
    • 1. VINBLASTINE
    • 2. VINCRISTINE
    • 3. VINORELBINE
    • 4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE)
    • 5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN)
    • 6. TAXANES (PACLITAXEL & DOCETAXEL)
  • 20. ANTIBIOTICS
    • 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN)
    • 2. DACTINOMYCIN(ACTINOMYCIN D)
    • 3. PLICAMYCIN(METHRAMYCIN
    • 4. MITOMYCIN (MITOMYCIN C)
    • 5. BLEOMYCIN
    • 6. EPIRUBICIN
    • 7. MITOZANTRONE
  • 21. HORMONAL AGENTS
    • A. ADRENOCORTICOIDS
    • 1. PREDNISONE
    • 2. HYDROCORTISONE
    • B. ANDROGENS
    • 1. TESTOSTERONE
    • 2.FLUOXYMESTERONE
    • C. ESTROGENS
    • 1. DIETHYLSTILBESTROL
    • 2. ETHINYL ESTRADIOL
    • D. PROGESTINS
    • 1. HYDROXYPROGESTERONE
    • 2.MEDROXYPROGESTERONE
  • 22. HORMONAL AGENTS
    • E. ESTROGEN INHIBITOR :
    • 1. TAMOXIFEN
    • 2. TORIMIFENE
    • F. ANDROGEN INHIBITOR
    • 1. FLUTAMIDE
    • 2.CYPROTERONE
  • 23. HORMONAL AGENTS
    • G. GONADOTROPIC RELEASING HORMONE AGONIST
    • (GnRH)
    • 1. LEUPROLIDE
    • 2. GOSERELIN
    • 3. NAFERELIN
    • H. AROMATASE INHIBITORS
    • 1. AMINOGLUTETHIMIDE & TRILOSTANE
    • 2. ANASTROZOLE
    • 3. LETROZOLE
    • 4.EXEMESTANE
  • 24. MISCELLANEOUS ANTI - CANCER DRUGS
    • 1. IMATINIB
    • 2. GROWTH FACATOR RECEPTOR INHIBITOR
    • A. CEFUXIMAB
    • B. GEFITINIB & ERLOTINIB
    • C. BEVACIZUMAB
    • 3. ASPARAGINASE (CRISANTASPASE)
    • 4. HYDROXYUREA
    • 5. RETINOIC ACID DERIVATIVE (TRETINOIN)
    • 6. ARSENIC TRIOXIDE
  • 25. MISCELLANEOUS ANTI - CANCER DRUGS
    • 6. BONE MARROW GROWTH FACTORS
    • GRANULOCYTE COLONY-STIMULATING FACTOR
    • (G-CSF, FILGRASTIM)
    • GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF, SARGAMOSTIM)
    • AMI FOSTINE (ETHYOL)
  • 26. MISCELLANEOUS ANTI - CANCER DRUGS
    • MONOCLONAL ANTIBODIES
    • 1. RIFUXIMAB
    • 2. TRASTUZUMAB
    • RADIOACTIVE ISOTOPES
    • RADIOACTIVE IODINE-TREATMENT OF THYROID CA
    • BIOLOGICAL RESPONSE MODIFIER
    • * INTERFERONS, ALDESLEUKIN, TRETINOIN
  • 27. ALKYLATING AGENTS
  • 28.
    • ALKYLATING AGENTS
    • I. PHARMACOKINETICS
      • oral or parenteral administration
      • hepatic microsome P450 mediated cyclophosphamide ACROLEIN…….MESNA
      • nitrosoureas: highly lipid soluble
      • unchanged form in urine (cisplatin)
      • terminated via hepatic metabolism: procarbazine
  • 29.
    • II. PHARMACODYNAMICS OF ALKYLATING AGENTS
    • CCNS: Form reactive molecules…> alkylation (N7 guanine)………>
    • Cross linking of bases
    • abnormal base pairing &
    • DNA strand breakage
    • RESISTANCE THRU:
    • ↑ DNA repair / ↓ drug permeability
    • production of trapping agents
  • 30.
    • ALKYLATING AGENTS
    • III. CLINICAL INDICATIONS
    • A. CYCLOPHOSPHAMIDE:
    • non Hodgskin’s lymphoma, breast & ovarian CA, neuroblastoma
    • B. MECHLORETHAMINE: Hodgskin ‘s disease (MOPP)
    • C. CARMUSTINE & LOMUSTINE: brain tumors
    • D. BUSULFAN: chronic myelogenous leukemia / Thiotep a: ovarian ca
  • 31.
    • IV. ADVERSE EFFECTS OF ALKYLATING AGENTS
    • NAUSEA & VOMITING Myelosuppression
    • hemorrhagic cystitis (cyclophosphamide)
    • peripheral neuropathy (altretamine))
    • adrenal insufficiency, pulmonary fibrosis & skin pigmentation (busulfan)
  • 32. RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS
    • PROCARBAZINE
    • in Hodgkin’s lymphoma
    • leukemogenic, teratogenic, mutagenic
    • N & V, myelosuppression, hemolytic anemia, pulmonary reaction, disulfiram like effect, skin rashes, CNS depression
  • 33.
    • B.CISPLATIN:
      • inorganic metal complex
      • In testicular CA, bladder, lung & ovarian CA
      • Nausea, vomiting, myelosuppression
      • Nephrotoxicity, neurotoxocity, ototoxicity, anaphylaxis
  • 34. ANTIMETABOLITES
  • 35.
    • .METHOTREXATE
    • PHARMACODYNAMICS
    • Inhibits dihydrofolate reductase…………..>
    • INTERFERES w/ thymidylate & purine nucleotide , serine, methionine
    • … > DNA synthesis & cell division block
    • RESISTANCE:
    • 1. ↓ drug accumulation
    • 2.change in drug sensitivity or activity of dihydrofolate reductase
    • 3. ↓ for mation of polyglutamates
  • 36. METHOTREXATE
    • PHARMACOKINETICS: Oral, IV. IM, intrathecal
    • CLINICAL USE: choriocarcinoma, acute leukemias, nonHodgskins and cutaneous T cell lymphomas, breast CA; rheumatoid arthritis, psoriasis & abortifacient
    • ADVERSE EFFECTS; N & V & D, mucositis
    • myelosuppression ; skin effects
    • reduced by folinic acid (leukoverin rescue)
    • enhance by salicylates, NSAID, sulfonamides, sulfonylureas
  • 37. MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)
    • 6 THIOINOSINIC ACID….activated by hypoxanthine - guanine phosphoribosyltransferase (HGPRT)….>
    • inhibit enzymes involved in purine metabolism
    • RESISTANCE:
    • decrease HGPRT activity
    • increase alkaline phosphatases that inactivate the toxic nucleotides
  • 38. MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG)
    • PHARMACOKINETCS: oral; urine
    • 6MP metabolism inhibited by allopurinol
    • CLINICAL INDICATIONS
    • acute leukemias ; chronic myelocytic leukemias
    • ADVERSE EFFECTS:
    • myelosuppression, immunosuppression, hepatotoxicity
  • 39. FLUOROURACIL ( 5FU)
    • Uracil, interferes with DTMP
    • ( 5 FDUMP)………..> thymidylate synthase….> “thymineless death” 5FdUTP….> DNA synthesis inhibition
    • RESISTANCE:
      • decreased activation of 5 FU
      • increased thymidylate synthase activity
      • reduce drug sensitivity of this enzyme
  • 40. FLUOROURACIL ( 5FU)
    • PHARMACOKINETICS : IV
    • widely distributed; hepatic metabolism
    • CLINICAL USES: colorectal, stomach, pancreas, esophagus, liver, bladder, breast, head and neck, liver & ovarian cancers
    • topical: keratoses & basal cell cancer
    • ADVERSE EFFECTS : myelosuppression, GIT effects & alopecia, hand & foot syndrome, neurotoxicity
  • 41. CYTARABINE (ARA-C)
    • activated to Ara CTP (inhibitor of DNA polymerase)
    • most S specific
    • RESISTANCE
    • ↓ uptake / ↓ conversion to Ara CTP
    • CLINICAL USE : acute leukemias
    • ADVERSE EFFECTS : myelosuppression & GIT irritation; neurotoxicity & peripheral neuritis
  • 42. PLANT DERIVATIVES
  • 43.
    • A. VINBLASTINE & VINCRISTINE
    • * Periwinkle plant
      • spindle poisons
      • prevent assembly of tubulin dimmers into microtubules
      • block formation of mitotic spindle
      • act on M phase
      • RESISTANCE: increase efflux of the drug
    • PHARMACOKINETICS
    • Parenterally
    • Hepatic metabolism
  • 44. A. VINBLASTINE & VINCRISTINE
    • CLINICAL USE
    • VINCRISTINE: MOPP & COP; acute leukemias, lymphomas, wilm’s tumor, choriocarcinoma
    • VINBLASTINE: ABVD; other lymphomas, neuroblastoma, testicular cancer, Kaposi’s sarcoma
    • VINORELBINE: advance non- small cell cancer
    • ADVERSE EFFECTS:
    • VINBLASTINE: GIT distress, alopecia, bone marrow suppression, alopecia
    • VINCRISTINE: neurotoxicity, areflexia, peripheral neuritis, paralytic ileus
  • 45. B. ETOPOSIDE & TENIPOSIDE
    • Podophyllotoxins from May apple root
    • interacts w/ topoisomerase II….>inhibits mitochondrial electron transport….> increase degradation of DNA
    • late S and early G2 phase
    • oral; elimination thru the kidneys
    • small cell lung CA, prostate & testicular CA
    • cause bone marrow suppression, GIT effects, alopecia
  • 46. C. TOPOTECAN & IRINOTECAN
        • from Comptotheca acuminate tree
        • inhibit topoisomerase I
        • DNA damage
        • Topotecan: advanced ovarian cancer, small cell lung cancer
        • Irinotecan: ,metastatic colorectal CA
        • Cause: myelosuppression & diarrhea
  • 47. D. PACLITAXEL & DOCETAXEL
      • Taxanes from Western yew
      • Prevent microtubule disassembly into tubulin monomers; by IV
      • Advanced breast and ovarian cancers
      • Paclitaxel : N & V, myelosuppression, peripheral neuropathy, hypersensitivity rx
      • Docetaxil : neurotoxicity & bone marrow suppression, fluid retention, rash
  • 48. ANTIBIOTICS
  • 49. A. DOXORUBICIN & DAUNORUBICIN
      • intercalate between base pairs………> inhibit topoisomerase II….>
      • generate free radicals …………> block synthesis of RNA & DNA…>
      • DNA strand scisision
      • Given IV; excreted in the bile & urine
  • 50. A. DOXORUBICIN & DAUNORUBICIN
      • DAUNORUBICIN: acute leukemias
      • DOXORUBICIN: ABVD; myelomas, sarcomas, breast, endometrial, lungs, ovarian & thyroid cancers
      • CARDIOTOXICITY ( USE DEXRAZOXANE, radical scavenger)
      • Bone marrow suppression, GIT effects, alopecia
  • 51. B. BLEOMYCIN
      • DNA strand breakage …..……>
      • inhibit DNA synthesis
      • CCS on G2 phase
      • USE: testicular cancer & Hodgskin’s lymphoma, lymphomas, squamous cell cancer
      • Hypersensitivity reaction, pulmonary dysfunction
  • 52. C. DACTINOMYCIN
    • binds to double-stranded DNA & inhibits DNA dependent RNA synthesis
    • USE: melanoma & wilm’s tumor
    • Causes bone marrow suppression, skin & GIT irritation
  • 53. D. MITOMYCIN
    • Activated to form an alkylating agent…> cross links DNA
    • IV given; hepatic metabolism
    • USE: adenocarcinoma of the cervix, stomach, pancreas & lungs
    • Causes myelosuppression
  • 54. HORMONAL AGENTS
  • 55. HORMONAL ANTICANCER AGENTS
    • A. GLUCOCORTICOIDS
    • Prednisone/ Hydrocortisone:
    • acute & chronic lymphocytic leukemias, hodgskin’s disease, other lymphomas
    • Fluid retention, hypertension, diabetes, Increase susceptibility to infection
  • 56. HORMONAL ANTICANCER AGENTS
    • B. SEX HORMONES
      • estrogen, progestins, androgens: hormone dependent cancers to change the hormone balance
      • Fluoxymesterone: advanced breast CA
      • Diethylstilbestrol: prostatic cancer
  • 57. HORMONAL ANTICANCER AGENTS
    • C. SEX HORMONES ANTAGONISTS
      • tamoxifen: estrogen receptor partial agonist
      • may cause nausea & vomiting, hot flushes, vaginal bleeding, hypercalcemia, ocular, dysfunction& peripheral edema
      • Flutamide: prostatic cancer
      • Cause:gynecomastia, hot flushes, hepatic dysfunction
  • 58. HORMONAL ANTICANCER AGENTS
    • D. GONADOTROPIN-RELEASING HORMONE ANALOGS (GnRh ANALOG)
      • Leuprolide, Goserelin & nafarellin
      • inhibit release of pituitary LH & FSH
      • prostatic cancer
      • may cause: bone pain, gynecomastia, hematuria, impotence & testicular atrophy
  • 59. HORMONAL ANTICANCER AGENTS
    • E. AROMATASE INHIBITORS
      • anastrozole & leterozole
      • inhibit enzyme that catalyzes the conversion of androstenedione to estrone
      • advanced breast cancer
      • diarrhea, nausea, hot flushes, bone & back pain, peripheral edema
  • 60.
        • MISCELLANEOUS ANTICANCER AGENTS
  • 61. MISCELLANEOUS ANTICANCER AGENTS
    • A. Asparaginase
      • depletes serum asparagines
      • used in leukemias & lymphomas
      • given IV
      • Cause severe hypersensitivity reactions, neurotoxicity & bleeding
  • 62. MISCELLANEOUS ANTICANCER AGENTS
    • B. IMATINIB
    • Inhibitor of the tyrosine kinase domain of the Bcr- Abl oncogenes & prevent the phosphorylation of the kinase substrate by ATP
    • For CML, GIT stromal tumors
    • N /V/D, Fluid Retention, Myalgia
  • 63. GROWTH FACTOR RECEPTOR INHIBITORS
    • A. CEFUZIMAB
    • Colorectal Ca
    • B. GEFITINIB & ERLOTINIB
    • NSCLCa
    • C. BEVACIZUMAB
    • Metastatic colororectal Ca
  • 64. MISCELLANEOUS ANTICANCER AGENTS
    • C. Interferons
      • endogenous glycoproteins with antineoplastic, immunosuppresion & antiviral actions
      • Use in hairy cell leukemias, chronic myelogenous leukemia, T cell lymphomas
      • Cause myelosuppression & neurologic dysfunction
  • 65. MISCELLANEOUS ANTICANCER AGENTS
    • D. Monoclonal Antibodies
      • RIFUXIMAB
      • Monoclonal antibody to a surface protein non- Hodgskin’s lymphoma cells
      • TRASTUZUMAB: monoclonal antibody to a surface protein in breast cancers that over express the HER2 protein
      • Toxicity: hypersensitivity reactions & myelosuppression
      • Cardiac dysfunction with trastuzumab
  • 66. STRATEGIES IN CANCER CHEMOTHERAPY
    • I. Each drug should be active when used alone against the particular cancer
    • II. The drug should have different mechanism of action
    • III. Cross resistant between drugs should be minimal.
    • IV. The drugs should have different toxic effects.
  • 67. SAMPLES OF COMBINATION CHEMOTHERAPY
    • . HODGKIN’S DISEASE: MOPP / ABVD
    • 2. NON-HODGKIN’S LYMPHOMA: COP
    • 3. TESTICULAR CARCINOMA: PVB
    • 4. BREAST CANCER: CMF/CAF
  • 68. CANCER CHEMOTHERAPY ACRONYMS
    • ABVD : Doxorubicin (adriamycin),
    • bleomycin, vinblastine, dacarbazine
    • CHOP :Cyclophosphamide, doxorubicin
    • (hydroxydaunorubicin), vincristine
    • (oncovin), Prednisone
    • MOPP : Melchlorethamine, vincristine
    • (oncovin), Procarbazine, Prednisone
  • 69. ACRONYMS
    • COP :Cyclophosphamide, vincristine (oncovin), prednisone
    • PEB: Platinuml(cisplatin),
    • etoposide bleomycin
    • CMF : Cyclophosphamide, methotrexate, Fluouracil
    • CAF: cyclophosphamide, adriamycin(doxorubicin) , 5 FU
  • 70. THE LEUKEMIAS
  • 71. 1. ACUTE LEUKEMIA
    • ALL: induction: vincristine & prednisone
    • >remission maintenance: mercaptopurine, methotrexate / cyclophosphamide
    • AML: cytarabine, mitoxantrone or daunorubicin or idarubicin
  • 72. 2.CHRONIC LEUKEMIA
    • CML: Imatinib, busulfan, or interferon
    • bone marrow transplant
    • CLL: chlorambucil & prednisone
    • fludarabine
  • 73. THE LYMPHOMAS
    • 1. HODGKIN’S DISEASE
      • MOPP
      • ABVD
    • 2. NON-HODGKIN’S LYMPHOMA
      • CHOP
    • MULTIPLE MYELOMA
    • melphalan & prednisone
  • 74. CARCINOMA OF THE BREAST
    • Stage I SURGERY
    • Stage II: positive lymph nodes: SURGERY plus cytotoxic chemo in 6 cycles at one month apart; CMF/CAF; tamoxifen in postmenopausal women
    • Trastazumab: HER-2/neu receptors
    • Stage III & IV Palliative
    • aminoglutethimide, trastuzumab
  • 75. CARCINOMA
    • WILM’S TUMOR : vincristine plus dactinomycin after surgery & radiotherapy
    • NEUROBLASTOMA : doxorubicin + cyclophosphamide + vincrisitne
    • CARCINOMA OF THE PANCREAS : gemcitarabine
    • POLYCYTHEMIA VERA : busulfan, chlorambucil or cyclophosphamide
  • 76. CARCINOMA
    • CHORIOCARCINOMA OF THE UTERUS :
      • Methotrexate / Etoposide & Cisplatin
    • CARCINOMA OF THE OVARY : cisplatin & paclitaxel
    • TESTICULAR NEOPLASMS : PEB
    • CARCINOMA OF THE PROSTATE
      • Estrogen, leuprolide & Flutamide
    • CARCINOMA OF THE THYROID
      • Radioiodine, doxorubicin & cisplatin
  • 77. CARCINOMA
    • GASTROINTESTINAL CARCINOMAS
    • Stomach: 5FU plus cisplatin
    • Colon: 5 FU + leucoverin + oxiplatin
    • MALIGNANT MELANOMA & MISC SARCOMAS:
      • dacarbazine & cisplain
    • BRAIN TUMORS
    • > carmustine, multimodality therapy
  • 78. LUNG CARCINOMA
    • Small cell( SCLCa)
    • Non-small cell(NSCLCa)75-80%
    • CISPLATIN & TAXANES
    • Others: methotrexate, vincristine, vinblastine, doxorubicin, mitomycin C
  • 79. THANK YOU VERY MUCH !!! Cast your burden on the Lord. And He shall sustain you He shall never permit the Righteous to be moved. Psalm 55 : 22