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ANTI ~ CANCER DRUGS

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

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ANTI ~ CANCER DRUGS

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

  7. ALKYLATING AGENTS Busulfan Carmustine Cyclophosphamide Lomustine Mechlorethamine Melphalan Thiothepa ANTHRACYCLINES Daunorubicin Doxorubicin Epirubicin Idarubicin Mitoxantrone ANTI TUMOR ANTIBIOTICS Dactinomycin Mitomycin Cell Cycle Non – Specific (CCNS) Agents • CAMPTOTHECINS • Irinotecan • Topotecan • PLATINUM ANALOGS • Carboplatin • Cisplatin • Oxaliplatin

  8. ANTIMETABOLITES Capecitabine Cladribine Cytarabine Fluorouracil Gemcitabine Mercaptopurine Methotrexate Thioguanine ANTITUMOR ANTIBIOTIC Bleomycin EPIPODOPHYLLO- TOXINS Etoposide Teniposide TAXANES Docetaxel Paclitaxel Cell Cycle Specific (CCS) Agents • VINCA ALKALOIDS • Vinblastine • Vincristine • Vinorelbine

  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

  10. CANCER CHEMOTHERAPEUTIC AGENTS C. CYTOTOXIC ANTIBIOTICS • microbial in origin • prevent cell division D. PLANT DERIVATIVES • affect microtubules and formation of mitotic spindle

  11. CANCER CHEMOTHERAPEUTIC AGENTS II. HORMONES • suppress hormone secretion • antagonize hormone action III. MISCELLANEOUS AGENTS

  12. CLASSIFICATION OF ANTI-CANCER DRUGS

  13. POLYFUNCTIONAL ALKYLATING AGENTS B. NITROSOUREA • CARMUSTINE(BNCU) 2. SEMUSTINE (methyl CCNU) 3.LOMUSTINE( CCNU) 4.STREPTOZOCIN A. NITROGEN MUSTARD 1. CYCLOPHOPHAMIDE 2. CHLORAMBUCIL 3. MECHLORETHAMINE 4. IFOSFAMIDE 5. MELPHALAN 6. ESTRAMUSTINE

  14. POLYFUNCTIONAL ALKYLATING AGENTS C.ALKYL SULFONATE 1. BUSULFAN D.AZIRIDINE 1. THIOTEPA E. TREOSULPHAN

  15. RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS • PROCARBAZINE • CISPLATIN • DACARBAZINE • CARBOPLATIN • ALTRETAMINE

  16. 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

  17. PLANT ALKALOIDS 1. VINBLASTINE 2. VINCRISITNE 3. VINORELBINE 4. PODOPHYLLOTOXINS (ETOPOSIDE & TENIPOSIDE) 5. CAMPTOTHECINS (TOPOTECAN & IRINOTECAN) 6. TAXANES (PACLITAXEL & DOCETAXEL)

  18. ANTIBIOTICS 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN) 2. DACTINOMYCIN(ACTINOMYCIN D) 3. PLICAMYCIN(METHRAMYCIN 4. MITOMYCIN (MITOMYCIN C) 5. BLEOMYCIN 6. EPIRUBICIN 7. MITOZANTRONE

  19. 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

  20. HORMONAL AGENTS E. ESTROGEN INHIBITOR : 1. TAMOXIFEN 2. TORIMIFENE F. ANDROGEN INHIBITOR 1. FLUTAMIDE 2.CYPROTERONE

  21. 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

  22. MISCELLANEOUS ANTI - CANCER DRUGS • ASPARAGINASE (CRISANTASPASE) 2. HYDROXYUREA 3. MITOTANE 4.AMSACRINE 5. RETINOID ACID DERIVATAIVES: TRETINOIN & ISOTRETINOIN

  23. 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)

  24. MISCELLANEOUS ANTI - CANCER DRUGS • MONOCLONAL ANTIBODIES 1. RIFUXIMAB 2. TRASTUZUMAB • RADIOACTIVE ISOTOPES • RADIOACTIVE IODINE-TREATMENT OF THYROID CA BIOLOGICAL RESPONSE MODIFIER * INTERFERONS, ALDESLEUKIN, TRETINOIN

  25. ALKYLATING AGENTS

  26. 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

  27. 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

  28. 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

  29. IV. ADVERSE EFFECTS OF ALKYLATING AGENTS • Myelosuppression/ N & V • hemorrhagic cystitis (cyclophosphamide) • peripheral neuropathy (altretamine)) • adrenal insufficiency, pulmonary fibrosis & skin pigmentation (busulfan)

  30. 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

  31. B.CISPLATIN: • inorganic metal complex • In testicular CA, bladder, lung & ovary CA • Nausea, vomiting, myelosuppression • Nephrotoxicity, neurotoxocity,ototoxicity, anaphylaxis

  32. ANTIMETABOLITES

  33. .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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. PLANT DERIVATIVES

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. ANTIBIOTICS

  47. 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

  48. 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

  49. 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

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