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Dr. Janet Fitzakerley Summer 2013 Med 6541 Hematopoiesis and Host Defences Antineoplastics [email protected] www.d.umn.edu/~jfitzake Page 1 of 11 DRUG PROPERTIES YOU NEED TO KNOW 1. Mechanism of action a. chemical class b. resistance DIFFERENCES ARE IMPORTANT!!!! 2. Pharmacokinetics 3. Therapeutic uses 4. Major side effects/toxicities AA 56-year-old56-year-old manman withwith non-Hodgkin’snon-Hodgkin’s lymphomalymphoma underwentunderwent aa successfulsuccessful coursecourse ofof therapytherapy withwith thethe CHOPCHOP regimen.regimen. 1.1. Which Which ofof thethe followingfollowing classesclasses ofof anticanceranticancer drugsdrugs isis cellcell cycle-cycle- nonspecificnonspecific (CCNS)(CCNS) andand usedused inin thethe CHOPCHOP regimen?regimen? A)A) Alkylating Alkylating agentsagents B)B) Vinca Vinca alkaloidsalkaloids C) Antimetabolites MECHANISMMECHANISM C) Antimetabolites D)D) Glucocorticoids Glucocorticoids E)E) Plant Plant alkaloidsalkaloids CHOPCHOP Cyclophosphamide THERAPEUTICTHERAPEUTIC Cyclophosphamide Doxorubicin USESUSES Doxorubicin VincristineVincristine (Oncovin)(Oncovin) PrednisonePrednisone AA 56-year-old56-year-old manman withwith non-Hodgkin’snon-Hodgkin’s lymphomalymphoma underwentunderwent aa successfulsuccessful coursecourse ofof therapytherapy withwith thethe CHOPCHOP regimen.regimen. 2.2. During During thethe secondsecond coursecourse ofof treatment,treatment, thisthis patientpatient developeddeveloped hemorrhagichemorrhagic cystitis.cystitis. TheThe mostmost likelylikely causitivecausitive agentagent is:is: A)A) Bleomycin Bleomycin B)B) Cyclophosphamide Cyclophosphamide C) Doxorubicin C) Doxorubicin TOXICITYTOXICITY D)D) Prednisone Prednisone E)E) Vincristine Vincristine Dr. Janet Fitzakerley Summer 2013 Med 6541 Hematopoiesis and Host Defences Antineoplastics [email protected] www.d.umn.edu/~jfitzake Page 2 of 11 NAMING CONVENTIONS Folate analogues = TREX METHOTREXATE, PEMETREXED, PRALATREXATE Antimetabolites = CITABINE and CAPECITABINE, CLADARABINE, ARABINE CYTARABINE, FLUDARABINE, GEMCITABINE Platinum-containing crosslinking agents = CISPLATIN, CARBOPLATIN, PLATIN OXALOPLATIN Anthracycline antibiotics = RUBICIN DAUNORUBICIN, DOXORUBICIN, EPIRUBICIN, IDARUBICIN Nitrosoureas = MUSTINE CARMUSTINE (BCNU), LOMUSTINE (CCNU) Taxanes = TAXEL PACLITAXEL, CABAZITAXEL, DOCATAXEL Antibiotics = MYCIN BLEOMYCIN, MITOMYCIN Camptothecins = TECAN IRINOTECAN, TOPOTECAN Vinca alkaloids = VIN...INE VINBLASTINE, VINCRISTINE, VINORELBINE = LIMUS TACROLIMUS, EVEROLIMUS, TEMSIROLIMUS Monoclonal antibodies = MAB too many to list here (there are others used as antineoplastics besides the ones you “need to know”) Signal transduction inhibitors (block the DASATINIB, ERLOTINIB, GEFITINIB, actions of tyrosine kinases) = NIB IMATINIB, LAPATANIB, NALOTINIB, PAZOPANIB, SORAFENIB, SUNITINIB Protein inhibitors = IB BORTEZOMIB Dr. Janet Fitzakerley Summer 2013 Med 6541 Hematopoiesis and Host Defences Antineoplastics [email protected] www.d.umn.edu/~jfitzake Page 3 of 11 DRUGS YOU NEED TO KNOW organized by chemical class = card colour (NB: Drugs in [] are related agents, parentheses indicate alternative names) METABOLITES & ANTIMETABOLITES 5-FLUOROURACIL [Capecitabine] THERAPEUTIC PROTEINS 6-MERCAPTOPURINE [Azothioprine] (“BIOLOGICS”) 6-THIOGUANINE ALEMTUZUMAB ALLOPURINOL L-ASPARAGINASE CLADRABINE BEVACIZUMAB CYTARABINE (ARA-C) CETUXIMAB / PANITUMUMAB FLUDARABINE DENILEUKIN DIFTITUX GEMCITABINE ERYTHROPOIETIN [Darbepoietin, MPEGepoietin] LEUCOVORIN FILGRASTIM [PEGFilgrastim] METHOTREXATE [Pemetrexed,Pralatrexate] INTERFERON ALKYLATING AGENTS INTERLEUKIN 2 INTERLEUKIN 11 BUSULFAN INTERLEUKIN-12 CARMUSTINE (BCNU) / LOMUSTINE (CCNU) RITUXIMAB [Ibritumomab, Tositumomab] CHLORAMBUCIL ROMIPLOSTIM CYCLOPHOSPHAMIDE [Ifosfamide] SARGRAMOSTIM (GM-CSF) DACARBAZINE TRASTUZUMAB MECHLORETHAMINE TUMOUR NECROSIS FACTOR MELPHALAN PROCARBAZINE MISCELLANEOUS TEMOZOLAMIDE ARSENIC TRIOXIDE NATURAL PRODUCTS BEXAROTENE BORTEZOMIB BLEOMYCIN CISPLATIN [Carboplatin, Oxaloplatin] DOXORUBICIN [Daunorubicin, Idarubicin, ERLOTINIB, GEFITINIB Epirubicin, Mitoxantone] HYDROXYUREA ETOPOSIDE IMATINIB [Dasatinib, Nilotinib] IRINOTECAN / TOPOTECAN LAPATINIB IXABEPILONE MESNA L-ASPARAGINASE PAZOPANIB, SUNITINIB MITOMYCIN SORAFENIB PACLITAXEL [Docataxel, Cabazitaxel] THALIDOMIDE VINBLASTINE [Vinorelbine] TRETINOIN VINCRISTINE VORINOSTAT IMMUNOSUPPRESSANTS CYCLOSPORINE, TACROLIMUS PREDNISONE, DEXAMETHASONE EVEROLIMUS, TEMSIROLIMUS MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 4 of 11 ACTION SITE MECHANISM DRUG (label colour) I. Block nucleotide Inhibit dihydrofolate Methotrexate synthesis (both purines Pemetrexed reductase and pyrimidines) Pralatrexate “Pseudofeedback 6-Mercaptopurine II. Block purine synthesis inhibition” of PNP and 6-Thioguanine PRPP Capecitabine Prevent DNA III. Block pyrimidine Inhibit thymidylate 5-Fluorouracil synthesis synthase Pemetrexed synthesis Pralatrexate Cytarabine IV. Block generation of Inhibit ribonucleotide Fludarabine deoxyribonucleotides reductase Gemcitabine Hydroxyurea Cladarabine Inhibit DNA V. Block DNA synthesis Cytarabine polymerase Fludarabine Gemcitabine Busulfan Carmustine (BCNU) Chlorambucil Cyclophosphamide Dacarbazine Ifosfamide Alkylating agents Lomustine (CCNU) Mechlorethamine I. Crosslink DNA Melphalan Mitomycin Procarbazine Temozolamide Disrupt DNA, Carboplatin Miscellaneous Cisplatin prevent DNA Oxaloplatin repair and/or Daunorubicin interfere with II. Intercalate or form Anthracycline antibiotic Doxorubicin Epirubicin RNA adducts with DNA (and related agents) Idarubicin synthesis Mitoxantone Free radical Bleomycin generation Form topoisomerase Etoposide III. Cause DNA strand II-DNA complexes breaks Irinotecan Inhibit topoisomerase I Topotecan Generate H2O2 (??) Procarbazine MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 5 of 11 Terminate spindle Vinblastine Vincristine Interrupt assembly Vinorelbine I. Disrupt spindle formation mitosis Enhance spindle Paclitaxel formation Ixabepilone Dexamethasone Glucocorticoids Prednisone Cyclosporine Antibiotics Tacrolimus I. Immunosuppressives Immune Alemtuzumab Denileukin diftitux system Antibodies Ibritumomab Rituximab modulators Tositumomab II. Immune system Interleukin 2 stimulants Cytokines Interferon α (hematopoietic agents listed Tumour necrosis factor α under supporting agents) Dasatinib Block bcr-abl Imatinib I. Target mutated or over- Nilotinib expressed proteins Lapatanib Block HER2 Trastuzumab II. Block growth factors or Cetuximab Erlotinib growth factor receptors Block EGFR Gefitinib Target altered (anti-VEGF listed under Lapatanib Prevent angiogenesis) proteins or Panitumumab Decrease FGF processes Interferon α production Deplete asaparagine L-asparaginase III. Target altered processes Inhibit 26S Bortezomib (blocking mTOR listed under proteosome prevent angiogenesis) Inhibit HDAC Vorinostat MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 6 of 11 Block VEGF Bevacizumab Pazopanib Block VEGF-R Sorafenib Prevent Sunitinib Everolimus angiogenesis Block mTOR Temsirolimus Interleukin-12 Miscellaneous Interferon α Thalidomide Retinoid Tretinoin Induce Rexinoid Bexarotene differentiation Miscellaneous Arsenic trioxide MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 7 of 11 Darbepoietin Erythroid growth Erythropoietin factors Peg-epoietin Filgrastim I. Hematopoietic agents Myeloid growth factors Pegfilgrastim Supporting Sagramostim agents Megakaryocyte growth Interleukin 11 factors Romiplostim Allopurinol II. Miscellaneous Leucovorin MESNA MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 8 of 11 ORGANIZATION OF ANTINEOPLASTICS ACCORDING TO PROTEIN FUNCTION PROTEIN NORMAL ACTION ANTINEOPLASTIC Hydrolysis of asparagine to aspartic L-asparaginase L-ASPARAGINASE acid and ammonia bcl-abl (non-receptor Activation of transcription factors via DASATANIB, IMATINIB, tyrosine kinase) cascade pathway NILOTINIB IBRITUMOMAB CD20 (B-lymphocyte restricted Transmembrane protein found on pre- RITUXIMAB differentiation antigen Bp35) B and mature B lymphocytes TOSITUMOMAB Sialic acid-dependent cytoadhesion CD33 (gp67, p67) molecule expressed by GEMTUZUMAB monocytic/myeloid lineage cells CAMPATH-1 antigen; GPI-anchored protein expressed at high levels on CD52 ALEMTUZUMAB thymocytes, lymphocytes, monocytes, and macrophages Allows calcineurin activation, Cyclophilin ultimately resulting in decreased CYCLOSPORINE secretion of IL-2 CYCLOPHOSPHAMIDE Hydroxylation of aromatic and PROCARBAZINE Cytochrome P450 aliphatic compounds (can activate or DOXORUBICIN inactivate antineoplastic drugs) PACLITAXEL Dihydropyrimidine Liver and gut enzyme that degrades 5-FLUOROURACIL dehydrogenase thymidine nucleotides Dihydrofolate reductase Converts dihydrofolate to METHOTREXATE (DHFR) tetrahydrofolate PEMETREXED Copies DNA templates during DNA CYTARABINE DNA Polymerase replication GEMCITABINE CETUXIMAB, ERLOTINIB, EGFR Binds epidermal growth factor GEFITINIB, LAPATANIB, PANITUMUMAB Fibroblast growth factor Angiogenic protein INTERFERON α (FGF) Allows calcineurin activation, FK-binding protein ultimately resulting in decreased TACROLIMUS secretion
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