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Just Drugs – Pharm 18-19 Want to know which drugs work on what part of the cycle. Cytotoxic Drug Toxicity Bone marrow suppression (doxorubicin, methotrexate, fluorouracil, docetaxel) Nausea/vomiting (cisplatin, doxorubicin) Hair loss (doxorubicin, paclitaxel) Cardiac toxicity (doxorubicin) Hemorrhagic cystitis (cyclophosphamide) Renal toxicity (cisplatin) Pulmonary toxicity (bleomycin) Neurotoxicity/neuropathy (vincristine, paclitaxel, ixabepilone) Alkylating Agents – cross-links DNA - not specific to cell cycle Transfer of alkyl group to DNA on N7 position of guanine in addition to other lesser sites; this leads to miscoding and strand breakage; crosslinks with DNA occurs with nitrosoureas after biotransformation Nitrogen mustard and the platinums create cross-links with DNA to inhibit DNA synthesis Antimetabolites Nitrogen Mustard Mechlorethamine *rarely used* Cyclophosphamide (most widely used), Ifosfamide MOA First chemotherapy agent Use PK AE Hodgkin’s lymphoma Additional Info chemical warfare. Effect rapid growing lymphoid cells Leukemia Non-Hodgkin’s lymphoma Breast, Lung, Ovarian Prodrugs converted to active agent by hepatic CYP 450 Immunosuppressant: RA Autoimmune nephritis Pre-transplantation Alopecia Nausea, Vomiting Bone marrow suppression Hemorrhagic cystitis: acrolein, a toxic metabolite, causes cystitis Mesna = antidote for cystitis – administered w/ chemo Ifosfamide 2nd line for: testicular & sarcoma Melphalan Bendamustine(newest agent, low toxicity profile) Dacarbazine Procarbazine Melphalan - Multiple Procarbazine – weak monoamine myeloma oxidase inhibitor Bendamustine – non-Hodgkin’s lymphoma Dacarbazine – replace procarbazine for non-Hodgkin’s lymphoma, melanoma bone marrow suppression sterility secondary leukemia, nausea and vomiting Procarbazine: multiple drug interactions and alcohol Nitrosourea: Carmustine, Lomustine, Streptozocin Carmustine/lomustine: Crosses BBB Brain tumors M: extensively Lymphoma Carmustine: Melanoma Multiple myeloma Streptozocin: Carcinoid tumor Pancreatic islet tumor Temozolamide (Temodar) Platinum Compounds: Cisplatin, Carboplatin, Oxaliplatin brain tumors (astrocytoma, glioblastoma) in conjunction with radiation 1st line for: Testicular, Ovarian, Cervical, Bladder, Lung Melanoma Carboplatin: Lung, Ovarian Oxaliplatin: Colorectal, pancreatic E: renally Carmustine/lomustine Can also affect IQ Myelosuppression (delayed & prolonged) w/ recovery of bone marrow at 6-8 wks. Thrombocytopenia – most severe Nausea & vomiting Pulmonary toxicity w/ high doses #1 drug to cause nausea & vomiting nausea and vomiting (cisplatin most toxic), renal toxicity (cisplatin), myelosuppression, peripheral neuropathy (oxaliplatin) peripheral neuropathy – hands go to sleep Antimetabolites –Most are analogs of purine or pyrimidine bases found in DNA or of folic acid Mechanism of action (MOA) – this class of drugs target the synthesis of DNA in the cancer cells Antimetabolites Methotrexate (prototype) MOA Structure similar to folic acid inhibit dihydrofolate reductase (required for T & purine synthesis) thereby interfering with RNA, DNA and cellular proteins Use PK Childhood leukemia A: variable, oral *Osteosarcoma D: variable in body water RA Lupus erythematosus Doesn’t cross BBB – can be administered intrathecally E: primarily as parent cmpnd in urine Premetrexed Antifolate Inhibits tetrahydrofolatedependent enzymes specifically thymidylate synthase Lung Pancreatic Colorectal Degraded in intestine & liver M: rapidly metabolized to active polyglutamate form AE Bone marrow suppression GI mucosa – mouth ulcers Additional Info *Leucovorin –used for rescue in high dose treatment before toxicity occurs Long term hepatotoxicity May crystallize in urine Bone marrow suppression - not as severe as alkylating agents toxicity by giving folic acid & B12 Can be used as a maintenance drug 5-FU/ Capecitabine (converted to5FU) Similar to Metorexate Binds to thymidylate synthase Purine analogs: Converted to nucleotide by catalyst impairs DNA synthesis 6-thioguanine & Mercaptopurine Blocks DNA synthesis and function Purine nucleoside analogues: Fludarabine, Cladribine, Metabolites incorporated into developing DNA Pyrimidine analogs: S phase specific, incorporated into DNA to stop replication and repair Cytarabine, Gemcitabine Chain termination Gemcitabine: several mechanisms of action Colorectal, anus breast stomac pancreas, esophagus Liver head and neck Leukemias (mostly in adults) Oral admin by food myelosuppression mucositis diarrhea skin toxicity (handfoot syndrome) neurotoxicity Bone marrow suppression Hepatotoxicity Leukemias Low-grade nonHodgkin’s lymphoma Cytarabine: Leukemia Gemcitabine: Pancreatic Non-small-cell lung Biliary tract gallbladder Breast Ovarian Carcinogenic myelosuppression immunosuppressive – take PCP prophylaxis during treatment and for 1 year after Bone marrow suppression Diarrhea Hand and foot syndrome – reddening of palms and feet DI – allopurinol Tumor cell can develop resistance by deleting this enzyme Mitotic Inhibitors MOA Binds to tubulin & Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine blocks polymerization Use PK Vincristine: Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Leukemia Multiple myeloma Small-cell lung Neuroblastoma Sarcoma AE Peripheral neuropathies Additional Info Vincristine/vinblastine Natural alkaloids from periwinkle plant, Vinorelbine – semisynthetic derivative of vinblastine Vinblastine: Lymphomas Bladder Breast, Ovarian Testicular Taxanes: Paclitaxel, Docetaxel Ixibepilone Binds to tubulin & prevents depolymerization in addition to taxane MOA, inhibits angiogenesis Vinorelbine: Non-small-cell carcinoma Paclitaxel *1st line: Metastatic ovarian Non-small-cell lung *2nd line: Metastatic breast Docetaxel: Breast Non-small-cell lung Breast resistance to taxanes, vinca alkaloids, & anthracyclines Eliminated by metabolism & biliary excretion metabolized and eliminated by fecal and renal excretion Myelosuppression Alopecia Paclitaxel derived from Pacific yew tree bark Neurotoxicity docetaxel – from needles of European yew fatigue, joint/muscle pain, alopecia, neurotoxicity, peripheral sensory neuropathy, myelosuppression Have to find the right pt for this! Pt can get very sick Antibiotics Anthracycline Drugs: Doxorubicin, Daunorubicin, Idarubicin epirubicin, mitoxantrone(less AE’s than others) MOA Use PK Intercalation of DNA inhibit topoisomerase Dauno & Ida: Myeloid leukemia D: rapidly to all body Myelosuppression tissues except CNS Cardiac damage M: extensively in liver – some Nausea & vomiting metabolites are active Alopecia Undergo reducation rxn form highly destructive hydroxyl radicals DNA damage Doxorubicin – very broad: Hodgkin’s Bladder Ovarian Gastric Some hematologic Long t1/2 AE Additional Info Mucosal ulceration Extravasation severe tissue ulceration/necrosis epirubicin – breast mitoxantrone – breast, non-Hodgkin’s lymphoma, acute myeloid leukemia Bleomycin (antibiotic) Active at G2 phase of cell cycle Hodgkin’s lymphoma D: widely Non-Hodgkin’s lymphoma Inactivated in cells by aminohydrolase – in skin & lung location of some toxicities Testicular E: renal Dactinomycin Antibiotic – prevents DNA transcription & mRNA synthesis Choriocarcinoma Pediatric tumors -Wilms’ tumor -Ewing’s sarcoma Pulmonary toxicity Mucocutaneous Skin hyperpigmentation Erythema Edema Potent, very good drug Stop immediately if drug is causing heart problems Chemistry – doxoand daunoantibiotics from Streptomyces peucetius, idarubicin, epirubicin, mitoxantrone are synthetic derivatives all have bright red color mixture of 2 peptides from Streptomyces verticillus; Topoisomerase Inhibitors permanent breaks in DNA – cell death! 2 groups Podopyllotoxins –inhibit type II(dsDNA), Camptothecin – inhibit type I(ssDNA) Topoisomerase Inhibitors Podopyllotoxins: MOA Inhibits type II Etoposide, Teniposide topoisomerase Use Etoposide: Testicular – 1st line Lung Non-Hodgkin’s lymphoma Bone marrow transplantation Synergistic w/ Cisplatin PK AE Etoposide: E: renal Additional Info Extracted from mandrake or mayapple plant; 2 semisynthetic derivatives Teniposide: M: hepatic Teniposide: Leukemias Camptothecin: inhibits type I Irinotecan, Topotecan topoisomerase Irinotecan: Colorectal Lymphomas Breast Cervical Gastric Lung Topotecan: Glioma Sarcoma Lung Ovarian Irinotecan: Rapidly metabolized to active metabolite Eliminated by bile Topotecan: Elimination by renal excretion Irinotecan: Myelosuppression Diarrhea Alopecia Mild nausea & vomiting Topotecan: Myelosuppression Alopecia Mild nausea & vomiting Camptotheca acuminata; synthetic derivatives are clinically useful – irinotecan and topotecan Protein Kinase Inhibitors – inhibits kinases involved w/ regulatory proteins blocks pathways promoting malignant transformation & proliferation VEGF: vascular endothelial growth factor o Wound healing Protein Kinase Inhibitors Imatinib, Dasatinib, Nilotinib Erlotinib Lapatinib Bortezomib MOA Use Inhibit BCR-ABL tyrosine kinase expressed by Philadelphia chrom. Renal cell carcinoma Imatinab: + inhibits ckit Highly specific for tyrosine kinase associated w/ epidermal growth factor receptor Kinase associated w/ HER2/neu receptor Inhibits proteasome & targets apoptosis inhibitors Imatinab: + GI stromal tumors *2nd line: Non-small-cell lung cancer PK Chronic Myeloid Leukemia Breast cancer Multiple myeloma M: CYP 450 3A4 AE Additional Info Monoclonal Antibodies Different mechanisms o Target growth factors or their receptors o Release cytotoxic drug or isotope o Enhance host immunity Must be given IV All expensive! Nomenclature o Letter before mab: o – mouse u – human xi – chimeric o Internal letter – therapeutic use tu – tumor vi – virus c or ci – circulation Monoclonal Antibodies Bevacizumab recombinant humanized antibody to vascular endothelial growth factor (VEGF) Rituximab: Chimeric human/murine to treat tumors First approved monoclonal ab to tx cancer Alemtuzumab Trastuzumab MOA Prevents binding of VEGF on endothelial cells inhibits blood vessel formation Use Colon cancer NSC lung cancer PK Bind to CD20 ag on surface of 90% of nonHodgkin’s lymphoma cells AE Additional Info GI bleeding Perforation Pulmonary hemorrhage Thromboembolic events First drug to target VEGF – doesn’t seem to make a different on survival Non-Hodgkin’s lymphoma Attached to radioactive isotopes to kill cancer cells Binds CD52 – found on Chronic lymphocytic all B & T lymphocytes leukemia & other leukocytes Extracellular Breast cancer HER2/neu receptor * 90Y-ibitumomab and 131-Itositumomab Chills, Fever NauseaVomiting Chest pain, Dyspnea Combind for Brest cancer “AC followed by T” Sorafenib, Sunitinib, Pazopanib small molecule inhibitors of tryosine kinases including some of the VEGF receptors and plateletderived growth factors Growth Factor Receptor inhibitors: Cetuximab, Panitumumab epidermal growth Cetuximab: factor receptor (EGFR) Colorectal inhibitors; Head overexpressed in solid Neck tumors (colorectal, head and neck, NSCLC, Panitumumab: pancreatic Colorectal Hormones & Antagonists Estrogen antagonists: Tamoxifen, Anastrozole, Letrozole, Leuprolide Androgen antagonists: Leuprolide, Flutamide, Nilutamide, Bicalutamide Corticosteroids MOA renal cell carcinoma hepatocellular carcinoma (sorafenib) gastrointestinal stromal tumors (sunitinib) Use Cancers that are hormone dependent may respond to antagonist Breast cancer Cancers that are hormone dependent may respond to antagonist Prostate cancer Lymphocytic leukemias Lymphomas M: All 3 are oral therapies liver CYP3A4 and have potential for multiple drug interactions hypertension, bleeding complications, fatigue sorafenib – skin rash and hand/foot syndrome sunitinib – cardiac dysfunction Infusion-related reactions Acne-like skin rash Currently used only with patients who have wild-type KRAS Hypertension Renal damage PK AE Additional Info