jfitzake@d.umn.edu Page 1 of 7 DRUGS YOU NEED TO KNOW ALKYLATING AGENTS (blue cards) BUSULFAN CARMUSTINE (BCNU) CYCLOPHOSPHAMIDE DACARBAZINE LOMUSTINE (CCNU) MECHLORETHAMINE MELPHALAN THIOTEPA NATURAL PRODUCTS (green cards) BLEOMYCIN DACTINOMYCIN DOORUBICIN ETOPOSIDE (VP-16) IRINOTECAN MITOMYCIN C PACLITAEL VINBLASTINE VINCRISTINE MISCELLANEOUS (white cards) ANGIOSTATIN AMSACRINE L-ASPARAGINASE BORTEZOMIB CARBOPLATIN CISPLATIN ERLOTINIB GEFITINIB HYDROYUREA IMATINIB PENTOSTATIN PROCARBAZINE THALIDOMIDE ANTIMETABOLITES AZATHIOPRINE 5-FLUOROURACIL 6-THIOGUANINE 6-MECAPTOPURINE CYTARABINE (ARA-C) GEMCITABINE METHOTREATE IMMUNOTHERAPY ALEMTUZUMAB AMINOGLUTETHIMIDE BEVACIZUMAB CETUIMAB CYCLOSPORINE DEAMETHASONE EDRECOLOMAB GEMTUZUMAB IBRITUMOMAB INTERFERON α INTERLEUKIN 2 INTERLEUKIN-12 PREDNISONE RITUIMAB TACROLIMUS (FK506) TOSITUMOMAB TRASTUZUMAB TUMOUR NECROSIS FACTOR α HORMONES and RELATED AGENTS AMINOGLUTETHIMIDE ANASTROZOLE EEMESTANE FLUTAMIDE LETROZOLE GOSERELIN LEUPROLIDE LETROZOLE TAMOIFEN SUPPORTING AGENTS ALLOPURINOL ERYTHROPOIETIN FILGRASTIM INTERLEUKIN 11 LEUCOVORIN MESNA SARGRAMOSTIM (GM-CSF)
jfitzake@d.umn.edu Page 2 of 7 ACTION SITE MECHANISM DRUG I. Nucleotide synthesis (both purines and pyrimidines) Inhibit folic reductase ( availability of single carbon fragments) Methotrexate Prevent DNA synthesis II. Purine synthesis III. Pyrimidine synthesis Inhibit purine ring biosynthesis Inhibit ribonucleotide reductase 6-Mercaptopurine 6-Thioguanine Pentostatin Gemcitabine Hydroxyurea Inhibit thymidylate synthase ( TMP synthesis) 5-Fluorouracil IV. DNA synthesis Inhibit DNA polymerase Cytosine Arabinoside Disrupt DNA, prevent DNA repair and/or interfere with RNA synthesis I. Cross-link DNA Busulfan Carboplatin Carmustine (BCNU) Cisplatin Cyclophosphamide Dacarbazine Lomustine (CCNU) Melphalan Mechlorethamine Mitomycin C Thiotepa II. Intercalate or form adducts with DNA III. Damage DNA and/or prevent repair (cause DNA strand breaks) Free radical generation Form topoisomerase II-DNA complexes Inhibit topoisomerase I Generate H 2 O 2 Inhibit adenosine deaminase Dactinomycin Daunorubicin Doxorubicin Bleomycin Amsacrine Etoposide Irinotecan Procarbazine Pentostatin
jfitzake@d.umn.edu Page 3 of 7 Interrupt mitosis I. Disrupt spindle formation Vinblastine Vincristine Paclitaxel I. Deplete L-asparagine L-Asparaginase II. Inhibit tyrosine kinases Block bcr-abl Imatinib Many (esp. EGFR) Erlotinib, Gefitinib Interfere with protein or hormone synthesis, function or secretion III. Inhibit proteosome IV. Decrease secretion of LH and FSH V. Decrease endogenous androgen concentrations and/or block effects ( antiandrogens ) VI. Decrease endogenous estrogen concentrations and/or block effects ( antiestrogens ) Decrease androgen synthesis Prevent translocation of androgen receptor Decrease synthesis of estrogens Inhibit binding of estradiol to the ER Bortezomib Leuprolide Goserelin Aminoglutethimide Flutamide Aminoglutethimide Exemestane Tamoxifen Immunotherapy Prevent angiogenesis I. Immunosuppresives Aminoglutethimide Azathioprine Cyclosporine Dexamethasone Prednisone Tacrolimus (Fk506) II. Interleukins Interleukins 2,11 III. Interferons IV. Tumor necrosis factors V. Block actions of proteins unique to cancer cells (monoclonal antibodies) CD52 CD33 CD20 CD20 HER2 Interferon α Tumor Necrosis Factor α Alemtuzumab Gemtuzumab Ibritumomab Rituximab Trastuzumab Angiostatin Interleukin-12 Interferon α Thalidomide
jfitzake@d.umn.edu Page 4 of 7 ORGANIZATION OF ANTINEOPLASTICS ACCORDING TO PROTEIN FUNCTION PROTEIN NORMAL ACTION ANTINEOPLASTIC Adenosine deaminase Conversion of adenosine to inosine PENTOSTATIN Adenine phosphoribosyltransferase Aromatase L-asparaginase bcl-abl (non-receptor tyrosine kinase) Calcineurin CD20 (B-lymphocyte restricted differentiation antigen Bp35) CD33 (gp67, p67) CD52 Salvage enzyme for reconversion of purines Convert androstenedione to estrone Hydrolysis of asparagine to aspartic acid and ammonia Activation of transcription factors via cascade pathway Activates NF-AT (activation factor for cytokine genes) Transmembrane protein found on pre- B and mature B lymphocytes Sialic acid-dependent cytoadhesion molecule expressed by monocytic/myeloid lineage cells CAMPATH-1 antigen; GPI-anchored protein expressed at high levels on thymocytes, lymphocytes, monocytes, and macrophages Purine analogs AMINOGLUTETHAMIDE, EEMESTANE L-ASPARAGINASE IMATINIB CYCLOSPORINE TACROLIMUS IBRITUMOMAB RITUIMAB GEMTUZUMAB ALEMTUZUMAB Cyclophilin Inhibits calcineurin CYCLOSPORINE Cytochrome P450 DNA Polymerase Dihydrofolate reductase (DHFR) Hydroxylation of aromatic and aliphatic compounds Copies DNA templates during DNA replication Converts dihydrofolate to tetrahydrofolate CYCLOPHOSPHAMIDE PROCARBAZINE DOORUBICIN CYTOSINE ARABINOSIDE METHOTREATE EGFR Binds epidermal growth factor ERLOTINIB, GEFITINIB FK-binding protein Inhibits calcineurin TACROLIMUS Glutathione peroxidase Oxidizes glutathione DOORUBICIN P-glycoprotein Drug transport out of cells Multidrug resistance HER2 Transmembrane protein overexpressed in breast cancer TRASTUZUMAB
jfitzake@d.umn.edu Page 5 of 7 ORGANIZATION OF ANTINEOPLASTICS ACCORDING TO PROTEIN FUNCTION (cont d) Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) 26S Proteosome Ribonucleotide reductase S-adenosyl-homocystein hydrolase Topoisomerase I Topoisomerase II Salvage enzyme for recoversion of purines Large protein complex that degrades ubiquitinated proteins Reduces nucleoside diphosphates to deoxy forms Hydrolyses S-adenosylhomocystein to adenosine and homocystein Binds to DNA and makes temporary breaks. Causes 2 nd half of double helix to pass through the break, and then reseals it. 6-MERCAPRTOPURINE 6-THIOGUANINE BORTEZOMIB GEMCITABINE HYDROYUREA Purine analogs PENTOSTATIN IRINOTECAN AMSACRINE DOORUBICIN ETOPOSIDE Thymidylate synthase TMP synthesis 5-FLUOROURACIL anthine oxidase Converts xanthine to uric acid 6-MERCAPTOPURINE HIGH (>90%) RELATIVE EMETIC POTENTIAL OF ANTINEOPLASTIC DRUGS MODERATELY HIGH (60-90%) MODERATE (30-60%) MODERATELY LOW (10-30%) Cisplatin Carmustine Asparaginase Bleomycin Androgens Mechlorethamine Cyclophosphamide Daunorubicin Etoposide Busulfan Dactinomycin Doxorubicin Hydroxyurea Estrogens Lomustine Fluorouracil Melphalan Progestins Mitomycin C 6-Mercaptopurine Methotrexate Vinblastine LOW (<10%)
jfitzake@d.umn.edu Page 6 of 7 Renal Toxicity Tumor lysis syndrome treat with allopurinol and vigorous oral hydration CISPLATIN proximal tubular damage resulting in magnesium and calcium loss treat by decreasing dose based on GFR, supplement with saline DRUG Protein Loss Toxin Buildup TYPE OF DAMAGE Ions and Water Reversible? Carmustine No Cisplatin Usually Cyclophosphamide Yes Lomustine No Methotrexate Yes Mitomycin No Vincristine Yes Neurotoxicity CISPLATIN can also cause dose related ototoxicity and a segmental demyelination resulting in a bilateral, symmetric peripheral neuropathy DRUG Asparaginase Carmustine Encephalopathies Autonomic Neuropathies Peripheral Neuropathies Cisplatin Arachnoiditis Cytarabine (IT) Etoposide 5-FU Methotrexate (IT) Procarbazine Vinblastine Vincristine
jfitzake@d.umn.edu Page 7 of 7 Hepatotoxicity DRUG Elevated Liver Enzymes Jaundice TYPE OF DAMAGE Hepatic Fibrosis Hepatitis, Necrosis Venocclusive Disease Asparaginase Azathioprine Busulfan Carmustine Cyclophosphamide Daunorubicin Mercaptopurine Methotrexate Mitomycin C 6-Thioguanine Cardiac Toxicity Acute: supra or ventricular tachycardias, transient decrease in ejection fractions Chronic: decreasing cardiac function over time (dose and schedule dependent) Risk factors: mediastinal radiation, history of hypotension, heart disease Ventric. Dysrhythm ECG changes Doxorubicin +++ +++ + + ++ Daunorubicin +++ +++ ++ + ++ Bleomycin + + Cisplatin + + Nitrogen Mustards ++ Spasm/ angina 5-Fu + + + + Methotrexate + Amsacrine ++ + + + DRUG CHF Cardiomyopathy Myo/pericarditis Bradycardia Hypotension Paclitaxel + + ++ ++