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Home , Melphalan, Mercaptopurine

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. 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) Vinca alkaloids B) Vinca alkaloids MECHANISM C)C) Antimetabolites MECHANISM D)D) Glucocorticoids Glucocorticoids E)E) Plant Plant alkaloidsalkaloids CHOPCHOP THERAPEUTICTHERAPEUTIC Cyclophosphamide 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 B)B) Cyclophosphamide Cyclophosphamide C) Doxorubicin C) Doxorubicin TOXICITYTOXICITY D)D) Prednisone Prednisone E)E) 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 , ,

Antimetabolites = CITABINE and , CLADARABINE, ARABINE , ,

Platinum-containing crosslinking agents = , , PLATIN OXALOPLATIN

Anthracycline antibiotics = RUBICIN , DOXORUBICIN, ,

Nitrosoureas = MUSTINE (BCNU), (CCNU)

Taxanes = TAXEL , , DOCATAXEL

Antibiotics = MYCIN BLEOMYCIN, MITOMYCIN

Camptothecins = TECAN ,

Vinca alkaloids = VIN...INE , VINCRISTINE,

= 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

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- [Capecitabine] THERAPEUTIC PROTEINS 6- [Azothioprine] (“BIOLOGICS”) 6-THIOGUANINE ALEMTUZUMAB L- 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 INTERLEUKIN-12 CARMUSTINE (BCNU) / LOMUSTINE (CCNU) RITUXIMAB [Ibritumomab, Tositumomab] ROMIPLOSTIM CYCLOPHOSPHAMIDE [] SARGRAMOSTIM (GM-CSF) TRASTUZUMAB MECHLORETHAMINE TUMOUR NECROSIS FACTOR  MISCELLANEOUS TEMOZOLAMIDE NATURAL PRODUCTS BORTEZOMIB BLEOMYCIN CISPLATIN [Carboplatin, Oxaloplatin] DOXORUBICIN [Daunorubicin, Idarubicin, ERLOTINIB, GEFITINIB Epirubicin, Mitoxantone] HYDROXYUREA IMATINIB [Dasatinib, Nilotinib] IRINOTECAN / TOPOTECAN LAPATINIB MESNA L-ASPARAGINASE PAZOPANIB, SUNITINIB MITOMYCIN SORAFENIB PACLITAXEL [Docataxel, Cabazitaxel] VINBLASTINE [Vinorelbine] VINCRISTINE 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 Inhibit dihydrofolate Methotrexate synthesis (both Pemetrexed reductase and pyrimidines) Pralatrexate “Pseudofeedback 6-Mercaptopurine II. Block 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 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 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 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 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 of IL-2

MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 9 of 11

Glutathione peroxidase Oxidizes glutathione DOXORUBICIN P-glycoprotein Drug transport out of cells Multidrug resistance 6-MERCAPTOPURINE Guanylyl kinase Converts GMP to GDP 6-THIOGUANINE Transmembrane protein LAPATINIB HER2 overexpressed in breast TRASTUZUMAB Removes acetyl groups from lysine residues leading to the formation of Histone deacetylase (HDAC) VORINOSTAT condensed and transcriptionally silenced chromatin - “Salvage” enzyme for recoversion of 6-MERCAPRTOPURINE phosphoribosyl transferase purines 6-THIOGUANINE (HGPRT) Interleukin 2 Cytokine that induces and expands a DENILEUKIN DIFTITUX (itself an antineoplastic) T cell response Intracellular serine/threonine kinase EVEROLIMUS mTOR involved in regulation of cell TEMSIROLIMUS proliferation and angiogenesis checkpoint that is mutated p53 gene product ALKYLATING AGENTS in 50% of human Fusion protein of retinoic acid ARSENIC TRIOXIDE PML-RARα receptor and promyelocytic protein TRETINOIN produced via translocation in APL Large protein complex that degrades 26S Proteosome BORTEZOMIB ubiquitinated proteins PRPP glutamyl 6-MERCAPTOPURINE 1st committed step in purine synthesis amidotransferase 6-THIOGUANINE Purine nucleoside 6-MERCAPTOPURINE 1st step in purine synthesis phosphorylase (PNP) 6-THIOGUANINE Pyrimidine monophosphate Converts UMP to UDP 5-FLUOROURACIL kinase Reduces nucleoside diphosphates to GEMCITABINE Ribonucleotide reductase deoxy forms HYDROXYUREA BEVACIXIMAB Receptor for vascular endothelial VEGF PAZOPANIB growth factor (needed for VEGF-R SORAFENIB angiogenesis) SUNITINIB Converts capecitabine to 5-FU Thymidine phosphorylase CAPECITABINE (preferentially in cancer cells)

MED 6762 Endocrine and Reproductive Systems Winter 2013 Dr. Janet Fitzakerley www.d.umn.edu/~jfitzake Antineoplastics [email protected] Page 10 of 11

Reversible nuclease that breaks Topoisomerase I phosphodiesterase bonds resulting in IRINOTECAN a transient single-strand break Makes a temporary DNA break, then DOXORUBICIN Topoisomerase II causes 2nd half of double helix to pass ETOPOSIDE through the break before resealing it. CAPECITABINE Thymidylate synthase TMP synthesis 5-FLUOROURACIL PEMETREXED Key component of mitotic spindle and IXABEPILONE, PACLITAXEL, Tubulin (axon transport, VINBLASTINE, VINCRISTINE cytoskeleton) ALLOPURINOL Converts xanthine to uric acid 6-MERCAPTOPURINE Vascular endothelial growth Angiogenic growth factor BEVACIXIMAB factor (VEGF)

Dr. Janet Fitzakerley Summer 2013 Med 6541 Hematopoiesis and Host Defences Antineoplastics [email protected] www.d.umn.edu/~jfitzake Page 11 of 11

CARDIOTOXICITY RENAL TOXICITY NEUROTOXICITY CHF Other Carmustine Asparaginase L-Asparaginase Doxorubicin Bleomycin Cisplatin Busulfan Carmustine Trastuzumab Cisplatin Cyclophosphamide Carmustine Cisplatin Ixabepilone Lomustine Cyclophosphamide Cytarabine Nitrogen mustards Methotrexate 6-Mercaptopurine Etoposide 5-Fluorouracil Vincristine Methotrexate 5-Fluorouracil Methotrexate 6-Thioguanine Ixabepilone Paclitaxel Methotrexate Paclitaxel Procarbazine Vinblastine Vincristine

RELATIVE EMETIC POTENTIAL OF ANTINEOPLASTIC DRUGS HIGH MODERATELY MODERATE MODERATELY LOW (>90%) HIGH (60-90%) (30-60%) LOW (10-30%) (<10%) Cisplatin Carmustine L-asparaginase Bleomycin Busulfan Mechlorethamine Cyclophosphamide Doxorubicin Etoposide Lomustine 5-Fluorouracil Hydroxyurea Melphalan 6-Mercaptopurine Methotrexate Vinblastine