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ANTI ~ CANCER DRUGS Zenaida N. Maglaya, MD, FPSECP
CANCER <ul><li>is a disease in which there in uncontrolled multiplication & spread within the body of abnormal forms of th...
Special Characteristics of  Cancer Cells <ul><li>Uncontrolled Proliferation </li></ul><ul><li>Dedifferentiation and loss o...
Management of Cancer <ul><li>Surgical </li></ul><ul><li>Irradiation </li></ul><ul><li>Chemotherapy </li></ul>
PHASES OF CELL CYCLE
Mitosis M Synthetic S Pre-Synthetic G 1 Post –Synthetic G 2 DIFFEREN-TIATION G 0
Cell Cycle Non – Specific (CCNS) Agents <ul><li>ALKYLATING </li></ul><ul><li>AGENTS </li></ul><ul><li>Busulfan </li></ul><...
Cell Cycle Specific (CCS) Agents <ul><li>ANTIMETABOLITES </li></ul><ul><li>Capecitabine </li></ul><ul><li>Cladribine </li>...
<ul><li>CCS:  </li></ul><ul><li>Hematological malignancies,  </li></ul><ul><li>solid tumors in growth fraction </li></ul><...
CANCER CHEMOTHERAPEUTIC AGENTS <ul><li>C. CYTOTOXIC ANTIBIOTICS </li></ul><ul><li>microbial in origin </li></ul><ul><li>pr...
 
 
CANCER CHEMOTHERAPEUTIC AGENTS <ul><li>II. HORMONES </li></ul><ul><li>suppress hormone secretion </li></ul><ul><li>antagon...
CLASSIFICATION OF ANTI-CANCER DRUGS
POLYFUNCTIONAL ALKYLATING AGENTS <ul><li>A. NITROGEN MUSTARD </li></ul><ul><li>1. CYCLOPHOPHAMIDE </li></ul><ul><li>2. CHL...
POLYFUNCTIONAL ALKYLATING AGENTS <ul><li>C.ALKYL SULFONATE </li></ul><ul><li>1. BUSULFAN </li></ul><ul><li>D.AZIRIDINE  </...
RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS <ul><li>PROCARBAZINE </li></ul><ul><li>CISPLATIN </li></ul><ul><li>DACA...
ANTIMETABOLITES <ul><li>A. FOLATE ANTAGONIST </li></ul><ul><li>1. METHOTREXATE </li></ul><ul><li>B. PURINE ANTAGONIST </li...
PLANT ALKALOIDS <ul><li>1. VINBLASTINE </li></ul><ul><li>2. VINCRISTINE </li></ul><ul><li>3. VINORELBINE </li></ul><ul><li...
ANTIBIOTICS <ul><li>1. ANTHRACYCLINES(DOXORUBICIN  & DAUNORUBICIN) </li></ul><ul><li>2. DACTINOMYCIN(ACTINOMYCIN D) </li><...
HORMONAL AGENTS <ul><li>A. ADRENOCORTICOIDS </li></ul><ul><li>1.  PREDNISONE </li></ul><ul><li>2. HYDROCORTISONE </li></ul...
HORMONAL AGENTS <ul><li>E. ESTROGEN INHIBITOR  : </li></ul><ul><li>1. TAMOXIFEN </li></ul><ul><li>2. TORIMIFENE </li></ul>...
HORMONAL AGENTS <ul><li>G. GONADOTROPIC RELEASING HORMONE AGONIST  </li></ul><ul><li>(GnRH) </li></ul><ul><li>1. LEUPROLID...
MISCELLANEOUS ANTI - CANCER DRUGS <ul><li>1. IMATINIB </li></ul><ul><li>2. GROWTH FACATOR RECEPTOR INHIBITOR </li></ul><ul...
MISCELLANEOUS ANTI - CANCER DRUGS <ul><li>6. BONE MARROW GROWTH FACTORS </li></ul><ul><li>GRANULOCYTE COLONY-STIMULATING F...
MISCELLANEOUS ANTI - CANCER DRUGS <ul><li>MONOCLONAL ANTIBODIES </li></ul><ul><li>1. RIFUXIMAB </li></ul><ul><li>2. TRASTU...
ALKYLATING AGENTS
<ul><li>ALKYLATING AGENTS </li></ul><ul><li>I. PHARMACOKINETICS </li></ul><ul><ul><li>oral or parenteral administration </...
<ul><li>II.  PHARMACODYNAMICS OF ALKYLATING  AGENTS </li></ul><ul><li>CCNS:  Form reactive molecules…> alkylation (N7 guan...
<ul><li>ALKYLATING AGENTS </li></ul><ul><li>III. CLINICAL INDICATIONS </li></ul><ul><li>A. CYCLOPHOSPHAMIDE:  </li></ul><u...
<ul><li>IV. ADVERSE EFFECTS OF ALKYLATING AGENTS   </li></ul><ul><li>NAUSEA & VOMITING Myelosuppression </li></ul><ul><li>...
RELATED DRUGS PROBABLY ACTING AS ALKYLATING AGENTS <ul><li>PROCARBAZINE </li></ul><ul><li>in Hodgkin’s lymphoma </li></ul>...
<ul><li>B.CISPLATIN:  </li></ul><ul><ul><li>inorganic metal complex </li></ul></ul><ul><ul><li>In  testicular CA, bladder,...
ANTIMETABOLITES
<ul><li>.METHOTREXATE </li></ul><ul><li>PHARMACODYNAMICS </li></ul><ul><li>Inhibits dihydrofolate reductase…………..> </li></...
  METHOTREXATE <ul><li>PHARMACOKINETICS:  Oral,  IV. IM, intrathecal  </li></ul><ul><li>CLINICAL USE:  choriocarcinoma, ac...
MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG) <ul><li>6 THIOINOSINIC ACID….activated by hypoxanthine - guanine phosphoribosyl...
MERCAPTOPURINE (6 MP) & THIOGUANINE (6 TG) <ul><li>PHARMACOKINETCS: oral; urine </li></ul><ul><li>6MP metabolism inhibited...
FLUOROURACIL  ( 5FU) <ul><li>Uracil,  interferes with  DTMP  </li></ul><ul><li>( 5 FDUMP)………..>  thymidylate synthase….> “...
 FLUOROURACIL  ( 5FU) <ul><li>PHARMACOKINETICS : IV </li></ul><ul><li>widely distributed; hepatic metabolism </li></ul><ul...
CYTARABINE (ARA-C) <ul><li>activated to Ara CTP (inhibitor of DNA polymerase) </li></ul><ul><li>most S specific </li></ul>...
PLANT DERIVATIVES
<ul><li>A. VINBLASTINE & VINCRISTINE </li></ul><ul><li>* Periwinkle plant </li></ul><ul><ul><li>spindle poisons </li></ul>...
A. VINBLASTINE & VINCRISTINE <ul><li>CLINICAL USE </li></ul><ul><li>VINCRISTINE: MOPP & COP; acute leukemias, lymphomas, w...
B. ETOPOSIDE  & TENIPOSIDE <ul><li>Podophyllotoxins from May apple root </li></ul><ul><li>interacts w/ topoisomerase II….>...
C.  TOPOTECAN  & IRINOTECAN <ul><ul><ul><li>from Comptotheca acuminate tree </li></ul></ul></ul><ul><ul><ul><li>inhibit to...
D. PACLITAXEL & DOCETAXEL <ul><ul><li>Taxanes from Western yew </li></ul></ul><ul><ul><li>Prevent microtubule disassembly ...
ANTIBIOTICS
A. DOXORUBICIN & DAUNORUBICIN <ul><ul><li>intercalate between base pairs………> inhibit topoisomerase II….> </li></ul></ul><u...
A. DOXORUBICIN & DAUNORUBICIN <ul><ul><li>DAUNORUBICIN: acute leukemias </li></ul></ul><ul><ul><li>DOXORUBICIN:  ABVD; mye...
B. BLEOMYCIN <ul><ul><li>DNA strand breakage …..……>  </li></ul></ul><ul><ul><li>inhibit DNA synthesis </li></ul></ul><ul><...
C. DACTINOMYCIN <ul><li>binds to double-stranded DNA  & inhibits DNA dependent RNA synthesis </li></ul><ul><li>USE: melano...
D. MITOMYCIN <ul><li>Activated to form an alkylating agent…> cross links DNA </li></ul><ul><li>IV given; hepatic metabolis...
HORMONAL AGENTS
HORMONAL ANTICANCER AGENTS <ul><li>A. GLUCOCORTICOIDS </li></ul><ul><li>Prednisone/ Hydrocortisone: </li></ul><ul><li>acut...
HORMONAL ANTICANCER AGENTS <ul><li>B. SEX HORMONES </li></ul><ul><ul><li>estrogen, progestins, androgens: hormone dependen...
HORMONAL ANTICANCER AGENTS <ul><li>C. SEX HORMONES ANTAGONISTS </li></ul><ul><ul><li>tamoxifen:  estrogen receptor partial...
HORMONAL ANTICANCER AGENTS <ul><li>D. GONADOTROPIN-RELEASING HORMONE ANALOGS (GnRh ANALOG) </li></ul><ul><ul><li>Leuprolid...
HORMONAL ANTICANCER AGENTS <ul><li>E. AROMATASE INHIBITORS </li></ul><ul><ul><li>anastrozole & leterozole </li></ul></ul><...
<ul><ul><ul><li>MISCELLANEOUS  ANTICANCER    AGENTS </li></ul></ul></ul>
MISCELLANEOUS ANTICANCER AGENTS <ul><li>A. Asparaginase </li></ul><ul><ul><li>depletes serum asparagines </li></ul></ul><u...
MISCELLANEOUS ANTICANCER AGENTS <ul><li>B. IMATINIB </li></ul><ul><li>Inhibitor of the tyrosine kinase domain of the Bcr- ...
GROWTH FACTOR RECEPTOR INHIBITORS <ul><li>A.  CEFUZIMAB </li></ul><ul><li>Colorectal Ca </li></ul><ul><li>B. GEFITINIB & E...
MISCELLANEOUS ANTICANCER AGENTS <ul><li>C. Interferons </li></ul><ul><ul><li>endogenous glycoproteins with antineoplastic,...
MISCELLANEOUS ANTICANCER AGENTS <ul><li>D. Monoclonal Antibodies </li></ul><ul><ul><li>RIFUXIMAB </li></ul></ul><ul><ul><l...
STRATEGIES IN CANCER CHEMOTHERAPY <ul><li>I. Each drug should be active when used alone against the particular cancer </li...
SAMPLES OF COMBINATION CHEMOTHERAPY <ul><li>. HODGKIN’S DISEASE: MOPP / ABVD </li></ul><ul><li>2. NON-HODGKIN’S LYMPHOMA: ...
CANCER CHEMOTHERAPY ACRONYMS <ul><li>ABVD : Doxorubicin (adriamycin), </li></ul><ul><li>  bleomycin, vinblastine, dacarbaz...
ACRONYMS <ul><li>COP :Cyclophosphamide, vincristine (oncovin), prednisone </li></ul><ul><li>PEB:  Platinuml(cisplatin), </...
THE LEUKEMIAS
1. ACUTE LEUKEMIA <ul><li>ALL: induction: vincristine & prednisone </li></ul><ul><li>>remission maintenance: mercaptopurin...
2.CHRONIC LEUKEMIA <ul><li>CML: Imatinib, busulfan, or interferon </li></ul><ul><li>bone marrow transplant </li></ul><ul><...
THE LYMPHOMAS  <ul><li>1. HODGKIN’S DISEASE </li></ul><ul><ul><li>MOPP </li></ul></ul><ul><ul><li>ABVD </li></ul></ul><ul>...
CARCINOMA OF THE BREAST <ul><li>Stage I  SURGERY </li></ul><ul><li>Stage  II:  positive lymph nodes: SURGERY plus cytotoxi...
CARCINOMA  <ul><li>WILM’S TUMOR : vincristine plus dactinomycin after surgery & radiotherapy </li></ul><ul><li>NEUROBLASTO...
CARCINOMA <ul><li>CHORIOCARCINOMA OF THE UTERUS : </li></ul><ul><ul><li>Methotrexate  /  Etoposide & Cisplatin </li></ul><...
CARCINOMA <ul><li>GASTROINTESTINAL CARCINOMAS </li></ul><ul><li>Stomach: 5FU plus  cisplatin </li></ul><ul><li>Colon: 5 FU...
LUNG CARCINOMA <ul><li>Small cell( SCLCa) </li></ul><ul><li>Non-small cell(NSCLCa)75-80% </li></ul><ul><li>CISPLATIN  & TA...
THANK YOU VERY MUCH !!! Cast your burden on the Lord. And He shall sustain you He shall never permit the Righteous to be m...
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Anti Cancer New Program

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Transcript of "Anti Cancer New Program"

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