CANCER • is a disease in which there in uncontrolled multiplication & spread within the body of abnormal forms of the body’s own cells. Special Characteristics of Cancer Cells • Uncontrolled Proliferation • Dedifferentiation and loss of function • Invasiveness • Metastasis Management of Cancer • Surgical • Irradiation • Chemotherapy PHASES OF CELL CYCLE DIFFERENTIATION Mitosis M G2 Synthetic S PreSynthetic G1 Post – Synthetic G0 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 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 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 CANCER CHEMOTHERAPEUTIC AGENTS C. CYTOTOXIC ANTIBIOTICS • microbial in origin • prevent cell division D. PLANT DERIVATIVES • affect microtubules and formation of mitotic spindle CANCER CHEMOTHERAPEUTIC AGENTS II. HORMONES • suppress hormone secretion • antagonize hormone action III. MISCELLANEOUS AGENTS CLASSIFICATION OF ANTI-CANCER DRUGS 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 POLYFUNCTIONAL ALKYLATING AGENTS C.ALKYL SULFONATE 1. BUSULFAN D.AZIRIDINE 1. THIOTEPA E. TREOSULPHAN RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS 1. 2. 3. 4. 5. PROCARBAZINE CISPLATIN DACARBAZINE CARBOPLATIN ALTRETAMINE ANTIMETABOLITES A. FOLATE ANTAGONIST 1. METHOTREXATE B. PURINE ANTAGONIST 1. MERCAPTOPURINE 2. THIOGUANINE 3. CLADRIBINE 4. FLUDARABINE 5. PENTOSTATIN C. PYRIMIDINE ANTAGONIST 1. FLUOROURACIL 2. CAPECITABINE 3. CYTARABINE 4. GEMCITABINE PLANT ALKALOIDS 1. VINBLASTINE 2. VINCRISITNE 3. VINORELBINE 4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE) 5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN) 6. TAXANES (PACLITAXEL & DOCETAXEL) ANTIBIOTICS 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN) 2. DACTINOMYCIN(ACTINOMYCIN D) 3. PLICAMYCIN(METHRAMYCIN 4. MITOMYCIN (MITOMYCIN C) 5. BLEOMYCIN 6. EPIRUBICIN 7. MITOZANTRONE 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 HORMONAL AGENTS E. ESTROGEN INHIBITOR : 1. TAMOXIFEN 2. TORIMIFENE F. ANDROGEN INHIBITOR 1. FLUTAMIDE 2.CYPROTERONE 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 MISCELLANEOUS ANTI - CANCER DRUGS 1. ASPARAGINASE (CRISANTASPASE) 2. HYDROXYUREA 3. MITOTANE 4.AMSACRINE 5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN 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) MISCELLANEOUS ANTI - CANCER DRUGS • MONOCLONAL ANTIBODIES 1. RIFUXIMAB 2. TRASTUZUMAB • RADIOACTIVE ISOTOPES • RADIOACTIVE IODINE-TREATMENT OF THYROID CA BIOLOGICAL RESPONSE MODIFIER * INTERFERONS, ALDESLEUKIN, TRETINOIN 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 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 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 IV. ADVERSE EFFECTS OF ALKYLATING AGENTS • Myelosuppression/ N & V • hemorrhagic cystitis (cyclophosphamide) • peripheral neuropathy (altretamine)) • adrenal insufficiency, pulmonary fibrosis & skin pigmentation (busulfan) 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 B.CISPLATIN: –inorganic metal complex –In testicular CA, bladder, lung & ovary CA –Nausea, vomiting, myelosuppression –Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis .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 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 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 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 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 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 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 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 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 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 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 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 ANTIBIOTICS 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 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 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 C. DACTINOMYCIN binds to double-stranded DNA & inhibits DNA dependent RNA synthesis USE: melanoma & wilm’s tumor Causes bone marrow suppression, skin & GIT irritation 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 HORMONAL ANTICANCER AGENTS A. GLUCOCORTICOIDS • Prednisone/ Hydrocortisone: • acute & chronic lymphocytic leukemias, hodgskin’s disease, other lymphomas • Fluid retention, hypertension, diabetes, Increase susceptibility to infection HORMONAL ANTICANCER AGENTS B. SEX HORMONES estrogen, progestins, androgens: hormone dependent cancers to change the hormone balance Fluoxymesterone: advanced breast CA Diethylstilbestrol: prostatic cancer 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 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 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 MISCELLANEOUS ANTICANCER AGENTS MISCELLANEOUS ANTICANCER AGENTS A. Asparaginase depletes serum asparagines used in leukemias & lymphomas given IV may cause severe hypersensitivity reactions, acute pancreatitis & bleeding MISCELLANEOUS ANTICANCER AGENTS B. Mitoxantrone alkylation of bases acute leukemias & breast cancer cause myelosuppression, GIT effects & cardiac arrythmias 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 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 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. SAMPLES OF COMBINATION CHEMOTHERAPY . HODGKIN’S DISEASE: MOPP / ABVD 2. NON-HODGKIN’S LYMPHOMA: COP 3. TESTICULAR CARCINOMA: PVB 4. BREAST CANCER: CMF/CAF CANCER CHEMOTHERAPY ACRONYMS • ABVD : Doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine • CHOP :Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), Prednisone • MOPP : Melchlorethamine, vincristine (oncovin), Procarbazine, Prednisone ACRONYMS • COP :Cyclophosphamide, vincristine (oncovin), prednisone • PEB: Platinuml(cisplatin), • etoposide bleomycin • CMF : Cyclophosphamide, methotrexate, Fluouracil • CAF: cyclophosphamide, adriamycin(doxorubicin) , 5 FU THE LEUKEMIAS 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 2.CHRONIC LEUKEMIA CML: Imatinib, busulfan, or interferon in younger patient: bone marrow transplant CLL: chlorambucil & prednisone fludarabine THE LYMPHOMAS 1. HODGKIN’S DISEASE MOPP ABVD 2. NON-HODGKIN’S LYMPHOMA CHOP > Mitoxantrone & Paclitaxel MULTIPLE MYELOMA melphalan & prednisone 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 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 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 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 LUNG CARCINOMA • • • • Small cell( SCLC) Non-small cell(NSCLC) CISPLATIN & TAXANES Others: methotrexate, vincristine, vinblastine, doxorubicin, mitomycin C 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