Zenaida N. Maglaya, MD, FPSECP

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Presentation transcript:

Zenaida N. Maglaya, MD, FPSECP ANTI ~ CANCER DRUGS Zenaida N. Maglaya, MD, FPSECP

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

G0 DIFFEREN-TIATION Mitosis M Pre-Synthetic Post –Synthetic G1 G2

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 ANTITUMOR ANTIBIOTIC Bleomycin EPIPODOPHYLLO- TOXINS Etoposide Teniposide TAXANES Docetaxel Paclitaxel ANTIMETABOLITES Capecitabine Cladribine Cytarabine Fluorouracil Gemcitabine Mercaptopurine Methotrexate Thioguanine 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 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 PROCARBAZINE CISPLATIN DACARBAZINE CARBOPLATIN ALTRETAMINE

ANTIMETABOLITES A. FOLATE ANTAGONIST B. PURINE 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

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 B. ANDROGENS C. ESTROGENS 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 ASPARAGINASE (CRISANTASPASE) 2. HYDROXYUREA 3. MITOTANE 4.AMSACRINE 5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN

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)

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

hepatic microsome P450 mediated cyclophosphamide ACROLEIN…….MESNA 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

Form reactive molecules…> alkylation (N7 guanine)………> 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

III. CLINICAL INDICATIONS A. CYCLOPHOSPHAMIDE: 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

Myelosuppression/ N & V hemorrhagic cystitis (cyclophosphamide) 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 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

ANTIMETABOLITES

.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

PLANT DERIVATIVES

prevent assembly of tubulin dimmers into microtubules 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 AGENTS

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

CML: Imatinib, busulfan, or interferon 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