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Cancer chemotherapy


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Cancer chemotherapy

  1. 1. CancerChemotherapy Jillian H. Davis Department of Pharmacology Howard University
  2. 2. Cell CycleCell Cycle Specific Agents Cell Cycle Non-Specific Agents• Antimetabolites • Alkylating Agents• Bleomycin • Antibiotics• Podophyllin Alkaloids •Cisplatin• Plant Alkaloids • Nitrosoureas
  3. 3. Resistance to Cytotoxic Drugs Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
  4. 4. Schematic of P-glycoprotein
  5. 5. Alkylating AgentsNitrogen Mustards Ethylenimines Alkyl Sulfonates NitrosoureasCyclophosphamide Thiotepa Busulfan Carmustine Legend Drug Class Sub-class Prototype Drug
  6. 6. Alkylating Agents Mechanism of Action Alkylate within DNA at the N7 position of guanine Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage Cross-linking of DNA and ring cleavage may also occur
  7. 7. Alkylating Agents Mechanism of Action
  8. 8. Nitrogen Mustards Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil
  9. 9. Cyclophosphamide Metabolism
  10. 10. Nitrosoureas Carmustine Lomustine Semustine Streptozocin-naturally occuring sugar containingM.O.A.- cross-link through alkylation of DNA All cross the blood brain barrier
  11. 11. Alkylating-Related Agents Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin
  12. 12. Platinum CoordinationComplexes These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl.
  13. 13. Alkylating Agents Toxicity Bone marrow depression, with leukopenia and thrombocytopenia Cyclophosphamide/Ifosfamide - hemorrhagic cystitis  Reduced by coadministration with MESNA Cisplatin/Carboplatin - ototoxic and nephrotoxic  Nephrotoxicity reduced by chloride diuresis and hydration
  14. 14. Alkylating Agents Therapeutic Uses Used to treat a wide variety of hematologic and solid tumors Thiotepa – ovarian cancer Busulfan – chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin – insulin-secreting islet cell carcinoma of the pancreas
  15. 15. AntimetabolitesFolic Acid Analogs Purine Analogs Pyrimidine Analogs Methotrexate Mercaptoguanine Fluorouracil Legend Drug Class Sub-class Prototype Drug
  16. 16. Folic Acid Analogs Methotrexate Trimetrexate Pemetrexed
  17. 17. Folate An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA To function as a cofactor folate must be reduced by DHFR to THF
  18. 18. Methotrexate Mechanism of Action The enzyme DHFR is the 1º site of action MTX prevents the formation of THF, causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis
  19. 19. Major Enzymatic Reactions Requiring Folates as Substrates* GAR transformylase AICAR transformylase AMP GAR AICAR IMP GMP (3) 10-formylTHF (2) Formate Methionine b + DHF THF e (1) c d dTMP 5,10-CH2THF 5-CH3THF a Homocysteine DNA dUMP a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase;*from Bowen d, methionine synthase; e, serine hydroxymethyl transferase
  20. 20. Resistance
  21. 21. Methotrexate Mechanism of Resistance1. Decreased drug transport2. Altered DHFR3. Decreased polyglutamate formation4. Increased levels of DHFR
  22. 22. Methotrexate Therapeutic Uses Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitt’s and non-Hodgkin’s lymphomas, cancers of the breast, head and neck, ovary, and bladder
  23. 23. Trimetrexate Therapeutic Uses Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung
  24. 24. Pemetrexed Therapeutic Uses Pemetrexed- Mesothelioma
  25. 25. Methotrexate Toxicity Bone marrow suppression  Rescue with leucovorin (folinic acid) Nephrotoxic  give sodium bicarbonate to alkalinize the urine
  26. 26. Purine Antagonists Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine
  27. 27. Mercaptopurine/Thioguanine Must metabolized by HGPRT to the nucleotide form This form inhibits numerous enzymes of purine nucleotide interconversion
  28. 28. Fludarabine Phosphate M.O.A.- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form The metabolite inhibits DNA polymerase-α and ribonucleotide reductase Induces apoptosis Tx- non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
  29. 29. Cladribine M.O.A. -phosphorylated by deoxycytidine kinase and is incorporated into DNA Causes DNA strand breaks Tx- hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma
  30. 30. Pyrimidine Antagonists Fluorouracil - S-phase Cytarabine Gemcitabine Capecitabine
  31. 31. MTX X 5-FU XFigure 2. This figure illustrates the effects of MTX and 5-FU on thebiochemical pathway for reduced folates.
  32. 32. Mechanism of Action 5-FU 5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate 5-FU is incorporated into DNA 5-FU inhibits RNA processing
  33. 33. Activation of 5-FU
  34. 34. Therapeutic Uses of 5-FU Metastatic carcinomas of the breast and the GI tract hepatoma carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas Combined with levamisole for Tx of colon cancer
  35. 35. Cytarabine It is activated to 5’ monophosphate (AraCMP) by deoxycytidine kinase Through a series of reactions it forms the diphosphate (AraCDP) and triphosphate (AraCTP) nucleotides Accumulation of AraCTP potently inhibits DNA synthesis Inhibition of DNA synthesis is due to competitive (-) of polymerases and interference of chain elongation
  36. 36. Cytarabine It is a potent inducer of tumor cell differentiation Fragmentation of DNA and evidence of apoptosis is noticed in treated cells AraC is cell-cycle specific agent, it kills cells in the S-phase
  37. 37. CytarabineMechanisms of Resistance deficiency of deoxycytidine kinase increased CTP synthase activity increased cytidine deaminase activity decreased affinity of DNA polymerase for AraCTP decrease ability of the cell to transport AraC
  38. 38. Cytarabine Therapeutic Uses Induction of remissions in acute leukemia Treats meningeal leukemia Treatment of acute nonlymphocytic leukemia In combination with anthracyclines or mitoxantrone it can treat non-Hodgkin’s lymphomas
  39. 39. Cytarabine Toxicities Nausea acute myelosuppression stomatitis alopecia
  40. 40. Gemcitabine Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate
  41. 41. Gemcitabine Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced cell death has characteristics of apoptosis
  42. 42. Gemcitabine Therapeutic Uses Gemcitabine treats a variety of solid tumors very effective in the treatment of pancreatic cancer small cell lung cancer carcinoma of the bladder, breast, kidney, ovary, and head and neck
  43. 43. CancerChemotherapy Jillian H. Davis Department of Pharmacology Howard University
  44. 44. Plant AlkaloidsVinca Alkaloids Podophyllotoxins Camptothecins Taxanes Vinblastine Etoposide Topotecan Paclitaxel
  45. 45. Vinca Alkaloids Vinblastine Vincristine Vinorelbine
  46. 46. Vinca AlkaloidsInhibit microtubules(spindle), causingmetaphase cell arrestin M phase. 3 3
  47. 47. Vinca Alkaloids Mechanism of Action Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents- M phase
  48. 48. Vinblastine Toxicity Nausea Vomiting Marrow depression Alopecia
  49. 49. Vinblastine Therapeutic Uses Systemic Hodgkin’s disease Lymphomas
  50. 50. Vincristine Toxicity Muscle weakness Peripheral neuritis
  51. 51. Vincristine Therapeutic Uses With prednisone for remission of Acute Leukemia
  52. 52. Vinorelbine Toxicity Granulocytopenia Therapeutic Uses non-small cell lung cancer
  53. 53. Podophyllotoxins Etoposide (VP-16) Teniposide (VM-26) Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple
  54. 54. Podophyllotoxins Mechanism of Action Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme
  55. 55. Podophyllotoxins Toxicity Nausea Vomiting Alopecia Hematopoietic and lymphoid toxicity
  56. 56. Podophyllotoxins Therapeutic Uses Monocytic Leukemia Testicular cancer Oat cell carcinoma of the lung
  57. 57. Camptothecins Topotecan Irinotecan
  58. 58. Camptothecins Mechanism of Action Interfere with the activity of Topoisomerase I Resulting in DNA damage Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38
  59. 59. Camptothecins Toxicity Topotecan  Neutropenia, thrombocytopenia, anemia Irinotecan  Severe diarrhea, myelosuppression
  60. 60. Camptothecins Therapeutic Uses Topotecan- metastatic ovarian cancer (cisplatin-resistant) Irinotecan- colon and rectal cancer
  61. 61. Taxanes Paclitaxel (Taxol) Docetaxel Alkaloid esters derived from the Western and European Yew
  62. 62. Taxanes Mechanism of Action Mitotic “spindle poison” through the enhancement of tubulin polymerization
  63. 63. Taxanes Toxicity Paclitaxel  Neutropenia, thrombocytopenia  Peripheral neuropathy Docetaxel  Bone marrow suppression  Neurotoxicity  Fluid retention
  64. 64. Taxanes Therapeutic Uses Paclitaxel- ovarian and advanced breast cancer Docetaxel- advanced breast cancer
  65. 65. Antibiotics Anthracyclines- Doxorubicin & Daunorubicin Dactinomycin Plicamycin Mitomycin Bleomycin
  66. 66. Anthracyclines Doxorubicin Daunorubicin
  67. 67. Anthracyclines Mechanism of Action High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical and oxygen radicals
  68. 68. Anthracyclines Toxicity Bone marrow depression Total alopecia Cardiac toxicity
  69. 69. Anthracyclines Therapeutic Uses Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma Daunorubicin- acute leukemia
  70. 70. Dactinomycin Mechanism of Action Binds to double stranded DNA through intercalation between adjacent guanine- cytosine base pairs Inhibits all forms of DNA-dependent RNA synthesis
  71. 71. Dactinomycin Toxicity Bone marrow depression Oral ulcers Skin eruptions Immunosuppression
  72. 72. Dactinomycin Therapeutic Uses Wilms’ tumors Gestational choriocarinoma with MTX
  73. 73. Plicamycin Mechanism of Action Binds to DNA through an antibiotic-Mg2+ complex This interaction interrupts DNA-directed RNA synthesis
  74. 74. Plicamycin Toxicity Hypocalcemia Bleeding disorders Liver toxicity
  75. 75. Plicamycin Therapeutic Uses Testicular cancer Hypercalcemia
  76. 76. Mitomycin Mechanism of Action Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that cross- links DNA
  77. 77. Mitomycin Toxicity Severe myelosuppression Renal toxicity Interstitial pneumonitis
  78. 78. Mitomycin Therapeutic Uses Squamous cell carcinoma of the cervix Adenocarcinomas of the stomach, pancreas, and lung 2nd line in metastatic colon cancer
  79. 79. Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations CCS drug that causes accumulation of cells in G2
  80. 80. Bleomycin Toxicity Lethal anaphylactoid reactions Blistering Pulmonary fibrosis
  81. 81. Bleomycin Therapeutic Uses Testicular cancer Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum Lymphomas Intracavitary therapy in ovarian and breast cancers
  82. 82. Hormonal AgentsEstrogen & Androgen Gonadotropin-Releasing Aromatase Inhibitors Inhibitors Hormone Agonists Tamoxifen Leuprolide Aminogluthethimide Legend Drug Class Sub-class Prototype Drug
  83. 83. Anti-Estrogens Tamoxifen (SERMs) Raloxifene (SERMs) Faslodex
  84. 84. Tamoxifen Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ERα and ERβ Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell cycle
  85. 85. Tamoxifen Toxicity Hot flashes Fluid retention nausea
  86. 86. Tamoxifen Therapeutic Uses Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease
  87. 87. Anti-Androgen Flutamide  Antagonizes androgenic effects  approved for the treatment of prostate cancer
  88. 88. Gonadotropoin-Releasing HormoneAgonists Leuprolide Goserelin
  89. 89. Gonadotropoin-Releasing HormoneAgonist Mechanism of Action Agents act as GnRH agonist, with paradoxic effects on the pituitary Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones Resulting in reduced testicular androgen synthesis
  90. 90. Gonadotropoin-Releasing HormoneAgonist Toxicity Gynecomastia Edema thromboembolism
  91. 91. Gonadotropoin-Releasing HormoneAgonist Therapeutic Uses Metastatic carcinoma of the prostate Hormone receptor-positive breast cancer
  92. 92. Aromatase Inhibitors Aminogluthethimide Anastrozole
  93. 93. Aminogluthethimide Mechanism of Action Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone Inhibits the extra-adrenal synthesis of estrone and estradiol Inhibits the enzyme aromatase that converts androstenedione to estrone
  94. 94. Aminogluthethimide Toxicity Dizziness Lethargy Visual blurring Rash Therapeutic Uses ER- and PR-positive metastatic breast cancer
  95. 95. Anastrozole A new selective nonsteroidal inhibitor of aromatase Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen
  96. 96. Miscellaneous AntiCancer Agents Asparaginase Hydroxurea Mitoxantrone Mitotane Retinoic Acid Derivatives Amifostine
  97. 97. Asparaginase An enzyme isolated from bacteria Causes catabolic depletion of serum asparagine to aspartic acid and ammonia Resulting in reduced blood glutamine levels and inhibition of protein synthesis Neoplastic cells require external source of asparagine Treats childhood acute leukemia Can cause anaphylactic shock
  98. 98. Hydroxyurea An analog of urea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia
  99. 99. Mitoxantrone Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer Causes cardiac toxicity
  100. 100. Mechanisms & Actions of UsefulChemotherapeutic Drugs in NeoplasticDisease