Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 1 of 8

DRUG PROPERTIES YOU NEED TO KNOW 1. Mechanism of action a. chemical class b. resistance 2. Pharmacokinetics

3. Therapeutic uses DIFFERENCES ARE IMPORTANT!!!! 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 Antimetabolites MECHANISM 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, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 2 of 8

DRUGS YOU NEED TO KNOW (organized by chemical class = card colour)

ALKYLATING AGENTS MISCELLANEOUS BUSULFAN AMSACRINE CARMUSTINE (BCNU) ARSENIC TRIOXIDE CYCLOPHOSPHAMIDE BORTEZOMIB DACARBAZINE CARBOPLATIN LOMUSTINE (CCNU) CISPLATIN MECHLORETHAMINE DASATINIB MELPHALAN ERLOTINIB THIOTEPA GEFITINIB HYDROXYUREA NATURAL PRODUCTS IMATINIB ALEMTUZUMAB MESNA ANGIOSTATIN NILOTINIB BEVACIXIMAB PENTOSTATIN BLEOMYCIN PROCARBAZINE CETUXIMAB THALIDOMIDE CYCLOSPORINE TRETINOIN DACTINOMYCIN DAUNORUBICIN METABOLITES & DOXORUBICIN ANTIMETABOLITES DENILEUKIN DIFTITUX 5-FLUOROURACIL EDRECOLOMAB 6-MERCAPTOPURINE ERYTHROPOIETIN 6-THIOGUANINE ETOPOSIDE (VP-16) ALLOPURINOL FILGRASTIM AZATHIOPRINE GEMTUZUMAB CYTARABINE (ARA-C) IBRITUMOMAB GEMCITABINE INTERFERON α LEUCOVORIN INTERLEUKIN 2 METHOTREXATE INTERLEUKIN 11 INTERLEUKIN-12 HORMONES and IRINOTECAN L-ASPARAGINASE RELATED AGENTS MITOMYCIN C ABARELIX PACLITAXEL AMINOGLUTETHIMIDE RITUXIMAB ANASTROZOLE SARGRAMOSTIM (GM-CSF) BICALUTAMIDE TACROLIMUS (FK506) EXEMESTANE THROMBOPOIETIN FLUTAMIDE TOSITUMOMAB LETROZOLE TRASTUZUMAB GOSERELIN TUMOUR NECROSIS FACTOR α LEUPROLIDE VINBLASTINE LETROZOLE VINCRISTINE TAMOXIFEN TOREMIFENE IMMUNOSUPPRESSANT STEROIDS AMINOGLUTETHIMIDE DEXAMETHASONE PREDNISONE Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 3 of 8

ACTION SITE MECHANISM DRUG (label colour)

I. Block nucleotide Inhibit dihydrofolate synthesis (both purines Methotrexate reductase and pyrimidines) “Pseudofeedback Azathioprine II. Block purine synthesis inhibition” of PNP and 6-Mercaptopurine Prevent DNA PRPP 6-Thioguanine III. Block pyrimidine Inhibit thymidylate synthesis 5-Fluorouracil synthesis synthase IV. Block generation of Inhibit ribonucleotide Hydroxyurea deoxyribonucleotides reductase Pentostatin (indirect) Cytarabine V. Block DNA synthesis Inhibit DNA polymerase Gemcitabine

Busulfan Carmustine (BCNU) Cyclophosphamide Dacarbazine Alkylating agents Lomustine (CCNU) I. Crosslink DNA Melphalan Mechlorethamine Thiotepa Disrupt DNA, Carboplatin prevent DNA Miscellaneous Cisplatin repair and/or Mitomycin C interfere with Anthracycline Daunorubicin II. Intercalate or form antibiotics Doxorubicin RNA adducts with DNA synthesis Others Dactinomycin Free radical generation Bleomycin

Form topoisomerase II- Amsacrine III. Cause DNA strand DNA complexes Etoposide breaks Inhibit topoisomerase I Irinotecan

Generate H2O2 (??) Procarbazine

Terminate spindle Vincristine Interrupt assembly Vinblastine I. Disrupt spindle formation mitosis Enhance spindle Paclitaxel formation Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 4 of 8

Aminoglutethimide Glucocorticoids Dexamethasone I. Immunosuppressives Prednisone Cyclosporine Antibiotics Tacrolimus Interleukin 2 Interleukin 11 Immune Cytokines system Interferon α Tumour necrosis factor α modulators Alemtuzumab II. Immune system Cetuximab stimulants Denileukin diftitux Edrecolomab Monoclonal antibodies Gemtuzumab Ibritumomab Rituximab Trastuzumab

I. Deplete L-asparagine L-asparaginase Interfere with Dasatinib protein II. Signal transduction Block bcr-abl Imatinib (tyrosine kinase) Gefitinib synthesis or inhibitors Erlotinib Block EGFR function Gefitinib III. Inhibit proteosome Bortezomib

Angiostatin Prevent Bevacizumab Interleukin-12 angiogenesis Interferon α Thalidomide

Retinoids Tretinoin Induce differentiation Miscellaneous Arsenic trioxide

Goserelin I. Decrease LH and FSH GnRH agonists Leuprolide secretion GnRH antagonist Abarelix Bicalutamide II. Anti-androgens Interfere with Flutamide hormone Aminoglutethimide III. Prevent estrogen Anastrazole function Inhibit aromatase synthesis Exemestane Letrozole Tamoxifen SERMS IV. Anti-estrogens Toremifiene SERD Fulvestrant Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 5 of 8

ORGANIZATION OF ANTINEOPLASTICS ACCORDING TO PROTEIN FUNCTION

PROTEIN NORMAL ACTION ANTINEOPLASTIC Adenosine deaminase Conversion of adenosine to inosine PENTOSTATIN Adenine phosphoribosyl- “Salvage” enzyme for reconversion of Purine analogs transferase purines AMINOGLUTETHAMIDE, Aromatase Convert androstenedione to estrone EXEMESTANE Hydrolysis of asparagine to aspartic L-asparaginase L-ASPARAGINASE acid and ammonia bcl-abl (non-receptor Activation of transcription factors via IMATINIB tyrosine kinase) cascade pathway Activates NF-AT (activation factor for CYCLOSPORINE Calcineurin cytokine genes) TACROLIMUS CD20 (B-lymphocyte restricted Transmembrane protein found on pre- IBRITUMOMAB differentiation antigen Bp35) B and mature B lymphocytes RITUXIMAB 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 Cyclophilin Inhibits calcineurin CYCLOSPORINE CYCLOPHOSPHAMIDE Hydroxylation of aromatic and PROCARBAZINE Cytochrome P450 aliphatic compounds DAUNORUBICIN DOXORUBICIN Copies DNA templates during DNA DNA Polymerase CYTOSINE ARABINOSIDE replication Dihydrofolate reductase Converts dihydrofolate to METHOTREXATE (DHFR) tetrahydrofolate EGFR Binds epidermal growth factor ERLOTINIB, GEFITINIB FK-binding protein Inhibits calcineurin TACROLIMUS DAUNORUBICIN Glutathione peroxidase Oxidizes glutathione DOXORUBICIN P-glycoprotein Drug transport out of cells Multidrug resistance Transmembrane protein HER2 TRASTUZUMAB overexpressed in breast cancer Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 6 of 8

ORGANIZATION OF ANTINEOPLASTICS ACCORDING TO PROTEIN FUNCTION (cont’d)

Hypoxanthine-guanine “Salvage” enzyme for recoversion of 6-MERCAPRTOPURINE phosphoribosyl transferase purines 6-THIOGUANINE (HGPRT) Large protein complex that degrades 26S Proteosome BORTEZOMIB ubiquitinated proteins Reduces nucleoside diphosphates to GEMCITABINE Ribonucleotide reductase deoxy forms HYDROXYUREA S-adenosyl-homocystein Hydrolyses S-adenosylhomocystein Purine analogs hydrolase to adenosine and homocystein PENTOSTATIN Topoisomerase I IRINOTECAN Binds to DNA and makes temporary AMSACRINE breaks. Causes 2nd half of double DAUNORUBICIN Topoisomerase II helix to pass through the break, and DOXORUBICIN then reseals it. ETOPOSIDE Thymidylate synthase TMP synthesis 5-FLUOROURACIL Xanthine oxidase Converts xanthine to uric acid 6-MERCAPTOPURINE

RELATIVE EMETIC POTENTIAL OF ANTINEOPLASTIC DRUGS HIGH MODERATELY MODERATE MODERATELY LOW (>90%) HIGH (60-90%) (30-60%) LOW (10-30%) (<10%) Cisplatin Carmustine Asparaginase Bleomycin Androgens Mechlorethamine Cyclophosphamide Daunorubicin Etoposide Busulfan Dactinomycin Doxorubicin Hydroxyurea Estrogens Lomustine Fluorouracil Melphalan Progestins Mitomycin C 6-Mercaptopurine Methotrexate Vinblastine

Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 7 of 8

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

TYPE OF DAMAGE

DRUG Protein Loss Toxin Buildup Ions and Reversible? Water Carmustine X X No Cisplatin X X Usually Cyclophosphamide X Yes Lomustine X No Methotrexate X Yes Mitomycin X X No Vincristine X Yes

Neurotoxicity

CISPLATIN can also cause dose related ototoxicity and a segmental demyelination resulting in a bilateral, symmetric peripheral neuropathy

DRUG Encephal- Autonomic Peripheral Arachnoiditis opathies Neuropathies Neuropathies Asparaginase X Carmustine X Cisplatin X X Cytarabine X X (IT) Etoposide X 5-FU X X Methotrexate X (IT) X Procarbazine X X Vinblastine X Vincristine X X X

Dr. Janet Fitzakerley Summer, 2007 MED 6510 Histopathology Antineoplastics I [email protected] www.d.umn.edu/~jfitzake Page 8 of 8

Hepatotoxicity

TYPE OF DAMAGE

Elevated Venocclusive Jaundice Hepatic Hepatitis, DRUG Liver Fibrosis Necrosis Disease Enzymes Asparaginase X X X Azathioprine X X X Busulfan X X Carmustine X Cyclophosphamide X X Daunorubicin X Mercaptopurine X X X Methotrexate X X X Mitomycin C X X 6-Thioguanine X X

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

CHF Cardio- Myo/peri- Brady- Ventric. ECG Spasm/ Hypo- DRUG myopathy carditis cardia Dysrhythm changes angina tension Doxorubicin +++ +++ + + ++ Daunorubicin +++ +++ ++ + ++ Bleomycin + + Cisplatin + + Nitrogen Mustards ++ 5-Fu + + + + Methotrexate + Amsacrine ++ + + + Paclitaxel + + ++ ++