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Breast Regimen – AC->T (Adriamycin/cyclophosphamide followed by Taxol) Doxorubicin 60 mg/m2 IV over 5-15min Q 21 days Cyclophosphamide 600 mg/m2 IV over 30 min Q21 days 80 mg/m2 IV over 30 min Q 7 days Day 1 x 4 cycles Followed by Paclitaxel Day 1 weekly x 12 cycles Antimetabolites – analogs of purine/pyrimidine synthesis Inhibits enzymes catalyzing DNA synthesis Antimetabolites 6-thioguanine & Mercaptopurine Methotrexate MOA Purine analog Use Leukemias PK Oral admin by food Converted to nucleotide by catalyst impairs DNA synthesis Tumor cell can develop resistance by deleting this enzyme Structure similar to Childhood leukemia folic acid inhibit dihydrofolate *Osteosarcoma reductase (required for T & purine RA synthesis) Lupus erythematosus AE Bone marrow suppression Additional Info DI – allopurinol Hepatotoxicity Carcinogenic A: variable D: variable in body water Doesn’t cross BBB – can be administered intrathecally E: primarily as parent cmpnd in urine Bone marrow suppression GI mucosa – mouth ulcers Long term hepatotoxicity May crystallize in urine *Leucovorin – rescue necessary in lethal/high dose tx Degraded in intestine & liver 5-FU Binds to thymidylate synthase Cancers of head & neck & throughout GI system Leukemias Blocks cell repair Fludarabine, Cladribine, Clofarabine, Nelarabine Premetrexed Hydroxyurea DNA damage & apoptosis Metabolites incorporated into developing DNA Gene termination Antifolate Inhibits tetrahydrofolatedependent enzymes Ribonucleotide inhibitor stops DNA synthesis Low-grade nonHodgkin’s lymphoma Lung Pancreatic M: rapidly metabolized to active polyglutamate form Colorectal Leukemia Bone marrow suppression toxicity by giving folic acid & B12 Ovarian cancer Melanoma Cytarabine, Fluorouracil, Capecitabine, Gemcitabine Pyrimidine analogs Cytarabine: Incorporated into DNA stop replication Fluorouracil: Blocks synthesis of thymidine & RNA Gemcitabine: S-phase inhibitor Sickle Cell anemia ( fetal hgb) Cytarabine: Leukemia Fluorouracil: Solid tumors Breast Colorectal & liver metastasis Gastric Squamous cell tumors of head & neck Capecitabine: Elimination by metabolism Bone marrow suppression Diarrhea Colon Breast Floxuridine colorectal Gemcitabine: Pancreatic Non-small-cell lung Biliary tract gallbladder Breast Ovarian Alkylating Agents – cross-links DNA strands by covalent bonds b/w alkyl groups of drug & guanine bases Nonspecific to state of cell cycle Antimetabolites Nitrogen Mustard *no longer used* MOA First chemotherapy Use PK AE Hodgkin’s lymphoma Effect rapid growing lymphoid cells Cyclophosphamide Leukemia (most widely used), Non-Hodgkin’s lymphoma Ifosfamide Breast Prodrugs converted to active agent by hepatic CYP 450 Alopecia Nausea Vomiting Lung Bone marrow suppression Ovarian Hemorrhagic cystitis Immunosuppressant: RA Autoimmune nephritis Pre-transplantation Other Nitrogen Mustards: Chlorambucil, Additional Info Mechlorethamine: Converted in body fluid to alkylating Ifosfamide 2nd line for: testicular & sarcoma Chlorambucil: Oral – leukemia Chlorambucil: Bone marrow suppression Mesna = antidote for cystitis – administered w/ chemo Meclorethamine, Melphalan Nitrosourea: Carmustine, Lomustine, Streptozocin intermediate Melphalan: Multiple myeloma Carmustine/lomustine: Crosses BBB Brain tumors M: extensively Lymphoma Carmustine: Melanoma Multiple myeloma Streptozocin: Carcinoid tumor Pancreatic islet tumor Platinum Compounds: Cisplatin, Carboplatin, Oxaliplatin Sterility Secondary leukemia Mechlorethamine: Hodgkin’s lymphoma Non-Hodgkin’s lymphoma 1st line for: Testicular Ovarian Cervical Bladder Lung E: renally Mechlorethamine: *NOT commonly used due to toxicity 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 Melanoma Carboplatin: Lung Ovarian Busulfan Oxaliplatin: Colorectal Myeloid leukemia Nausea Mild vomiting Myelosuppression Pulmonary fibroses (5 Dacarbazine m. survival) Nausea Hodgkin’s Disease Vomiting Mitomycin Myelosuppression Myelosuppression Breast (salvage) Non-small-cell lung Severe pulmonary damage Pancreatic Hemolytic uremic syndrome Stomach Anthracycline Drugs: Doxorubicin, Daunorubicin, Idarubicin Bright red color Intercalation of DNA inhibit topoisomerase Undergo reducation rxn form highly destructive hydroxyl radicals DNA damage Anthracycline: Doxorubicin – very broad: Hodgkin’s Bladder Ovarian Gastric Some hematologic D: rapidly to all body tissues except CNS M: extensively in liver – some metabolites are active Long t1/2 Active at G2 phase of cell cycle Myelosuppression Cardiac damage Nausea & vomiting Alopecia Mucosal ulceration Breast Extravasation severe tissue ulceration/necrosis Less potent free radical formation less cardiotoxicity Hodgkin’s lymphoma D: widely *less AE overall compared to other Anthracyclines Pulmonary toxicity Non-Hodgkin’s lymphoma Inactivated in cells by aminohydrolase – in skin & lung location of some Acute myeloid leukemia Mitoxantrone Bleomycin Bladder Dauno & Ida: Myeloid leukemia Testicular Mucocutaneous Skin hyperpigmentation Potent, very good drug Stop immediately if drug is causing heart problems toxicities Erythema E: renal Dactinomycin Mitotic Inhibitors Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine Antibiotic – prevents DNA transcription & mRNA synthesis MOA Binds to tubulin & blocks polymerization Edema Choriocarcinoma Pediatric tumors – Wilms’ tumor, Ewing’s sarcoma Use PK AE Vincristine: Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Leukemia Multiple myeloma Small-cell lung Neuroblastoma Sarcoma Vinblastine: Lymphomas Bladder Breast Ovarian Testicular Taxanes: Paclitaxel, Docetaxel Binds to tubulin & prevents depolymerization Vinorelbine: Non-small-cell carcinoma Paclitaxel *1st line: Metastatic ovarian Non-small-cell lung *2nd line: Metastatic breast Eliminated by metabolism & biliary excretion Myelosuppression Alopecia Neurotoxicity Additional Info Ixibepilone Semisynthetic analogue of epothilone B binds beta-tubulin subunits Suppress microtubule actions Also inhibits angiogenesis Docetaxel: Breast Non-small-cell lung Breast resistance to taxanes, vinca alkaloids, & anthracyclines M: fecal & renal excretion Neurotoxicity – microtubules involved w/ nerve conduction Alopecia Unique toxicities: Fatigue Joint/muscle pain Hand-foot syndrom Topoisomerase Inhibitors permanent breaks in DNA Topoisomerase Inhibitors Podopyllotoxins: MOA Inhibits type II Etoposide, Teniposide topoisomerase Camptothecin: Use Etoposide: Testicular Lung Non-Hodgkin’s lymphoma Bone marrow transplantation Synergistic w/ Cisplatin Teniposide: Leukemias Irinotecan: PK AE Etoposide: E: renal Teniposide: M: hepatic Irinotecan: Irinotecan: Additional Info Irinotecan, Topotecan Colorectal Lymphomas Breast Cervical Gastric Lung Topotecan: Glioma Sarcoma Lung Ovarian Rapidly metabolized to active metabolite Eliminated by bile Topotecan: Elimination by renal excretion Myelosuppression Diarrhea Alopecia Mild nausea & vomiting Topotecan: Myelosuppression Alopecia Mild nausea & vomiting Protein Kinase Inhibitors – inhibits kinases involved w/ regulatory proteins blocks pathways promoting malignant transformation & proliferation Protein Kinase Inhibitors Imatinib, Dasatinib, Nilotinib Erlotinib Sunitinib, Sorafenib MOA Inhibit BCR-ABL tyrosine kinase expressed by Philadelphia chrom. Imatinab: + inhibits ckit Highly specific for tyrosine kinase associated w/ epidermal growth factor receptor Inhibit multiple kinases: VEGFR Use PK Chronic Myeloid Leukemia Imatinab: + GI stromal tumors *2nd line: Non-small-cell lung cancer Renal cell carcinoma Sunitinib: M: CYP 450 3A4 AE Additional Info c-kit Gefitinib Lapatinib Bortezomib GI stromal tumor Epidermal growth factor receptor Kinase associated w/ HER2/neu receptor Inhibits proteasome & targets apoptosis inhibitors Sorafenib: Hepatocellular carcinoma NSC lung Breast cancer Multiple myeloma 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 Rituximab: MOA Chimeric human/murine to treat tumors Bind to CD20 ag on surface of 90% of nonHodgkin’s lymphoma cells First approved monoclonal ab to tx cancer Attached to radioactive isotopes to kill cancer cells Use Non-Hodgkin’s lymphoma PK AE Additional Info Alemtuzumab Gentozumab ozogamicin Trastuzumab Binds CD52 – found on Chronic lymphocytic all B & T lymphocytes leukemia & other leukocytes Conjugated to a Acute myeloid leukemia cytotoxic antibiotic Binds CD33 on hematopoietic cells complex internalized in lysosomes antibiotic release Extracellular HER2/neu receptor Breast cancer Chills Fever Nausea Vomiting Chest pain Cetuximab, Bevacizumab, Panitumumab Cetuximab: Colorectal Head Neck Bevacizumab: Colorectal Lung Brain Bevacizumab Prevents binding of VEGF on endothelial cells inhibits blood vessel formation Dyspnea Infusion-related reactions Acne-like skin rash Hypertension Renal damage Panitumumab: Colorectal Colon cancer GI bleeding NSC lung cancer Perforation Pulmonary hemorrhage First drug to target VEGF – doesn’t seem to make a different on survival Thromboembolic events Cytokine & Interferons: Interferons – endogenous proteins that increase activity of cytotoxic cells in immune system Cytokines & Interferons Interferon alpha2b Aldesleukin MOA Use Inhibits expression of oncogenes suppresses cell growth reduces cell proliferation Kaposi’s sarcoma Activates IL-2 receptors Renal cell carcinoma Hairy cell leukemia Melanoma Melanoma PK AE Leukopenia Thrombocytopenia Flu-like syndrome Nausea Vomiting Tiredness Altered taste Diarrhea Depression Hypotension Fluid retention Renal dysfunction Additional Info Start patients on anti-depressants to avoid depression Promotes B- & T-cell proliferation & differentiation destroy tumor cells Hormones & Antagonists Estrogen antagonists: MOA Use Breast cancer Tamoxifen, Anastrozole, Letrozole, Leuprolide Androgen antagonists: Prostate cancer Leuprolide, Flutamide, Nilutamide, Bicalutamide Corticosteroids Hematologic deficiencies Skin lesions Neuropsychiatric changes Reverse/prevent toxicity w/ corticosteroids before therapy Colorectal cancer Lymphocytic leukemias Lymphomas PK AE Additional Info