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Slide 2: CANCER • is a disease in which there in uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells.
Slide 3: Special Characteristics of Cancer Cells • Uncontrolled Proliferation • Dedifferentiation and loss of function • Invasiveness • Metastasis
Slide 4: Management of Cancer • Surgical • Irradiation • Chemotherapy
Slide 5: PHASES OF CELL CYCLE
Slide 6: Mitosis M PreSynthetic Post – Synthetic DIFFERENTIATION G0 G1 G2 S Synthetic
Slide 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
Slide 8: Cell Cycle Specific (CCS) Agents ANTIMETABOLITES • Capecitabine • Cladribine • Cytarabine • Fluorouracil • Gemcitabine • Mercaptopurine • Methotrexate • Thioguanine ANTITUMOR ANTIBIOTIC • Bleomycin EPIPODOPHYLLOTOXINS • Etoposide • Teniposide • TAXANES • Docetaxel • Paclitaxel VINCA ALKALOIDS • Vinblastine • Vincristine • Vinorelbine
Slide 9: CANCER CHEMOTHERAPEUTIC AGENTS I. CYTOTOXIC AGENTS A. ALKYLATING AGENTS AND RELATED COMPOUNDS • form covalents bonds with DNA • impede DNA replication B. ANTIMETABOLITES • block or subvert one or more of the metabolic pathways involved in DNA synthesis
Slide 10: CANCER CHEMOTHERAPEUTIC AGENTS C. CYTOTOXIC ANTIBIOTICS • microbial in origin • prevent cell division D. PLANT DERIVATIVES • affect microtubules and formation of mitotic spindle
Slide 12: CANCER CHEMOTHERAPEUTIC AGENTS II. HORMONES • suppress hormone secretion • antagonize hormone action III. MISCELLANEOUS AGENTS
Slide 13: CLASSIFICATION OF ANTI-CANCER DRUGS
Slide 14: POLYFUNCTIONAL ALKYLATING AGENTS A. NITROGEN MUSTARD 1. CYCLOPHOPHAMIDE 2. CHLORAMBUCIL 3. MECHLORETHAMINE 4. IFOSFAMIDE 5. MELPHALAN 6. ESTRAMUSTINE B. NITROSOUREA 1. CARMUSTINE(BNCU) 2. SEMUSTINE (methyl CCNU) 3.LOMUSTINE( CCNU) 4.STREPTOZOCIN
Slide 15: POLYFUNCTIONAL ALKYLATING AGENTS C.ALKYL SULFONATE 1. BUSULFAN D.AZIRIDINE 1. THIOTEPA E. TREOSULPHAN
Slide 16: RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS 1. 2. 3. 4. 5. PROCARBAZINE CISPLATIN DACARBAZINE CARBOPLATIN ALTRETAMINE
Slide 17: ANTIMETABOLITES A. FOLATE ANTAGONIST 1. METHOTREXATE B. PURINE ANTAGONIST 1. MERCAPTOPURINE 2. THIOGUANINE 3. CLADRIBINE 1. FLUOROURACIL 2. CAPECITABINE 4. FLUDARABINE 5. PENTOSTATIN C. PYRIMIDINE ANTAGONIST 3. CYTARABINE 4. GEMCITABINE
Slide 18: PLANT ALKALOIDS 1. VINBLASTINE 2. VINCRISITNE 3. VINORELBINE 4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE) 5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN) 6. TAXANES (PACLITAXEL & DOCETAXEL)
Slide 19: ANTIBIOTICS 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN) 2. DACTINOMYCIN(ACTINOMYCIN D) 3. PLICAMYCIN(METHRAMYCIN 4. MITOMYCIN (MITOMYCIN C) 5. BLEOMYCIN 6. EPIRUBICIN 7. MITOZANTRONE
Slide 20: 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
Slide 21: HORMONAL AGENTS E. ESTROGEN INHIBITOR : 1. TAMOXIFEN 2. TORIMIFENE F. ANDROGEN INHIBITOR 1. FLUTAMIDE 2.CYPROTERONE
Slide 22: 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
Slide 23: MISCELLANEOUS ANTI - CANCER DRUGS 1. ASPARAGINASE (CRISANTASPASE) 2. HYDROXYUREA 3. MITOTANE 4.AMSACRINE 5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN
Slide 24: MISCELLANEOUS ANTI - CANCER DRUGS 6. BONE MARROW GROWTH FACTORS • GRANULOCYTE COLONYSTIMULATING FACTOR (G-CSF, FILGRASTIM) • GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF, SARGAMOSTIM) • AMI FOSTINE (ETHYOL)
Slide 25: MISCELLANEOUS ANTI - CANCER DRUGS • MONOCLONAL ANTIBODIES 1. RIFUXIMAB 2. TRASTUZUMAB • RADIOACTIVE ISOTOPES • RADIOACTIVE IODINE-TREATMENT OF THYROID CA BIOLOGICAL RESPONSE MODIFIER * INTERFERONS, ALDESLEUKIN, TRETINOIN
Slide 27: 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
Slide 28: II. PHARMACODYNAMICS OF ALKYLATING AGENTS CCNS  Form reactive molecules…> alkylation (N7 guanine)………>  Cross linking of bases, abnormal base pairing & DNA strand breakage RESISTANCE THRU: increased DNA repair decrease drug permeability production of trapping agents 
Slide 29: 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
Slide 30: IV. ADVERSE EFFECTS OF ALKYLATING AGENTS • Myelosuppression/ N & V • hemorrhagic cystitis (cyclophosphamide) • peripheral neuropathy (altretamine)) • adrenal insufficiency, pulmonary fibrosis & skin pigmentation (busulfan)
Slide 31: RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS A. PROCARBAZINE • in Hodgkin’s lymphoma • leukemogenic, teratogenic, mutagenic • N & V, myelosyppression, hemolytic anemia, pulmonary reaction, disulfiram like,skin rashes, CNS depression
Slide 32: B.CISPLATIN: –inorganic metal complex –In testicular CA, bladder, lung & ovary CA –Nausea, vomiting, myelosuppression –Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis
Slide 34: .METHOTREXATE PHARMACODYNAMICS • Inhibits dihydrofolate reductase…………..> • INTERFERES w/ thymidylate & purine nucleotide • …> DNA synthesis & cell division block RESISTANCE: • 1. decrease drug accumulation • 2.change in drug sensitivity or activity of dihydrofolate reductase • 3. decrease formation of polyglutamates
Slide 35: 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 • bone marrow suppression ; skin effects • reduced by folinic acid (leukoverin rescue) • enhance by salicylates, NSAID, sulfonamides, sulfonylureas
Slide 36: 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
Slide 37: 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
Slide 38: FLUOROURACIL ( 5FU) • Uracil, interferes with DTMP • ( 5 FDUMP)………..> thymidylate synthase….> “thymineless death”………..> DNA synthesis inhibition RESISTANCE: – decreased activation of 5 FU – increased thymidylate synthase activity – reduce drug sensitivity of this enzyme
Slide 39: 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
Slide 40: CYTARABINE (ARA-C) • activated to Ara CTP (inhibitor of DNA polymerase) • most S specific RESISTANCE • 1.decreased uptake • 2. decreased conversion to Ara CTP CLINICAL USE: acute leukemias ADVERSE EFFECTS: myelosuppression & GIT irritation; neurotoxicity & peripheral neuritis
Slide 42: 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
Slide 43: 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 VINCRISTINE: neurotoxicity, areflexia, peripheral neuritis, paralytic ileus
Slide 44: 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
Slide 45: 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
Slide 46: 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
Slide 47: ANTIBIOTICS
Slide 48: 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
Slide 49: 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
Slide 50: 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
Slide 51: C. DACTINOMYCIN binds to double-stranded DNA & inhibits DNA dependent RNA synthesis USE: melanoma & wilm’s tumor Causes bone marrow suppression, skin & GIT irritation
Slide 52: 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
Slide 54: HORMONAL ANTICANCER AGENTS . GLUCOCORTICOIDS Prednisone/ Hydrocortisone: acute & chronic lymphocytic leukemias, hodgskin’s disease, other lymphomas Fluid retention, hypertension, diabetes, Increase susceptibility to infection
Slide 55: HORMONAL ANTICANCER AGENTS B. SEX HORMONES estrogen, progestins, androgens: hormone dependent cancers to change the hormone balance Fluoxymesterone: advanced breast CA Diethylstilbestrol: prostatic cancer
Slide 56: HORMONAL ANTICANCER AGENTS C. SEX HORMONES ANTAGONISTS – tamoxifen: estrogen receptor oartial agonist – may cause nausea & vomiting, hot flushes, vaginal bleeding, hypercalcemia, ocular, dysfunction& peripheral edema – Flutamide: prostatic cancer – Cause:gynecomastia, hot flushes, hepatic dysfunction
Slide 57: 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
Slide 58: 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
Slide 59: MISCELLANEOUS ANTICANCER AGENTS
Slide 60: MISCELLANEOUS ANTICANCER AGENTS A. Asparaginase  depletes serum asparagines  used in leukemias & lymphomas  given IV  may cause severe hypersensitivity reactions, acute pancreatitis & bleeding
Slide 61: MISCELLANEOUS ANTICANCER AGENTS B. Mitoxantrone alkylation of bases acute leukemias & breast cancer cause myelosuppression, GIT effects & cardiac arrythmias
Slide 62: 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
Slide 63: 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
Slide 64: 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. STRATEGIES IN CANCER CHEMOTHERAPY
Slide 65: SAMPLES OF COMBINATION CHEMOTHERAPY . HODGKIN’S DISEASE: MOPP / ABVD 2. NON-HODGKIN’S LYMPHOMA: COP 3. TESTICULAR CARCINOMA: PVB 4. BREAST CANCER: CMF/CAF
Slide 66: CANCER CHEMOTHERAPY ACRONYMS • ABVD : Doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine • CHOP :Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), Prednisone • MOPP : Melchlorethamine, vincristine (oncovin), Procarbazine, Prednisone
Slide 67: • COP :Cyclophosphamide, vincristine (oncovin), prednisone • PEB: Platinuml(cisplatin), • etoposide bleomycin • CMF : Cyclophosphamide, methotrexate, Fluouracil • CAF: cyclophosphamide, adriamycin(doxorubicin) , 5 FU ACRONYMS
Slide 68: THE LEUKEMIAS
Slide 69: 1. ACUTE LEUKEMIA CHILDHOOD LEUKEMIA > ALL: induction: vincristine & prednisone >remission maintenance: mercaptopurine, methotrexate & cyclophosphamide in various combination ADULT LEUKEMIA > AML: cytarabine, mitoxantrone or daunorubicin or idarubicin
Slide 70: 2.CHRONIC LEUKEMIA CML: Imatinib, busulfan, or interferon in younger patient: bone marrow transplant CLL: chlorambucil & prednisone fludarabine
Slide 71: THE LYMPHOMAS 1. HODGKIN’S DISEASE  MOPP  ABVD 2. NON-HODGKIN’S LYMPHOMA  CHOP  > Mitoxantrone & Paclitaxel MULTIPLE MYELOMA  melphalan & prednisone
Slide 72: CARCINOMA OF THE BREAST Stage I SURGERY Stage II: positive lymph nodes: SURGERY plus cytotoxic chemo in 8 cycles at one month apart; CMF/CAF; tamoxifen in postmenopausal women Stage III & IV Palliative aminoglutethimide, trastuzumab
Slide 73: CARCINOMA WILM’S TUMOR: vincristine lus dactinomycin after surgery >Methotrexate, cyclophosphamide, doxorubicin NEUROBLASTOMA: doxorubicin + cyclophosphamide + vincrisitne CARCINOMA OF THE PANCREAS: gemcitarabine POLYCYTHEMIA VERA: busulfan, chlorambucil or cyclophosphamide
Slide 74: 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
Slide 75: CARCINOMA GASTROINTESTINAL CARCINOMAS • Stomach: 5FU plus doxorubicin & mitomycin • Colon: 5 FU plus leucoverin or interferon MALIGNANT MELANOMA & MISC SARCOMAS: – dacarbazine & cisplain BRAIN TUMORS • > carmustine, multimodality therapy
Slide 76: LUNG CARCINOMA • • • • Small cell( SCLC) Non-small cell(NSCLC) CISPLATIN & TAXANES Others: methotrexate, vincristine, vinblastine, doxorubicin, mitomycin C
Slide 77: 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