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Anti-Cancer Drugs

Antineoplastic Agents

Alkylating agents ? * Nitrogen mustard - cyclophosphamide and mechlorethamine ..... * procarbazine
Antimetabolites ? * Antifolates - methotrexate .... * Pyrimidine antimetabolites - cytarabine..... * Purine antimetabolites - 6-mercaptopurine, 6-thioguanine, fludarabine
Natural products ? * Antimitotic drugs - vincristine and vinblastine
Antibiotics ? * doxorubicin - daunorubicin - idarubicin
Enzymes ? * L-asparginase
Retinoids ? * ATRA
Glucocorticoids ? * prednisone and dexamethasone
Antibodies ? * rituximab
Protein tyrosine kinase inhibitors ? * imatinid and dasatinib
Histone deacetylase (HDAC) inhibitors ? * vorinostat
Proteasome inhibitors ? * bortezomib
MOA of Alkylating agents ? * alkylate the N7 position of guanine in DNA and cross-links covalently bind two together --> causes strand breaks and apoptosis
why the toxicity ? * excessive cross-linking
Alkylating Agents SEs ? * potentially carcinogenic, can cause sterility, VOD (venous occlusive disease)of liver
Nitrogen mustards - Alkylating agent MOA and SEs ? * cross link DNA.... * SEs = see BM depression (dose related)
Cyclophosphamide ? * most versatile and used alkylating agent and is used in lots of cancers .... * Requires hepatic activation (P450) -- a prodrug requiring metabolic activation in the liver
Cyclophosphamide metabolism metabolites ? * phosphoramide mustard = anti-cancer metab .... * acrolein - toxic metab where we see bladder hemorrhaging
Cyclophosphamide SEs ? * BM depression ..... * Hemorrhagic Cystitis - treat with hydration and of Mesna or N-acetylcysteine (NAC)
Mechlorethamine basics and SEs ? * not as broad spectrum as Cyclophos ..... * See high emetic frequency with even looking at this drug
procarbazine use ? * Treatment of Hodgkin lymphoma
Procarbazine MOA ? * Inhibits DNA, RNA, and protein synthesis ---- Inhibits transmethylation of methyl groups of methionine into transfer RNA
Procarbazine – Side effects ? * CNS toxicity and disulfiram-like reaction ( puke with alcohol) ...... * Inhibits MAO - watch tyramine rich foods in these pts.
Antimetabolites general MOA and SEs? * act by starving the DNA precursors so they can't be used .... * see BM depression and GI issues
Antifolates - methotrexate use ? * leukemias, lymphomas, and RA
MTX MOA ? * Folic acid analog (antagonist) --- inhibits dihydrofolate reductase (DHFR) ---> loss of TMP
High Dose Methotrexate ? * Used for CNS prophylaxis in pts with leukemia and high-risk lymphoma.... * give with Leucovorin --> reduces toxicity (DHFR inhibition) in normal cells and gives the body back its folate
MTX SEs ? * BMD and GI ulcerations
Pyrimidine Antimetabolites - cytarabine uses and SEs ? * Prodrug converted to ara-CTP competes with dCTP & inhibits DNA synthesis and is rapidly cleared, constant infusion is needed.... * Uses: Hematological (AML, ALL, NHL) .... * SEs = BMD and HYPERuricemia
Purine analogs - 6-Mercaptopurine and 6-thioguanine uses ? * AML, ALL, CML
6-Mercaptopurine and 6-thioguanine MOA ? * turns in to a nucleotide analog and then inhibits synthesis of purine nucleotides --> leads to decreased RNA & DNA synthesis..... * inhibits the rate limiting step of guanine synthesis, IMPDH
6-mercaptopurine also blocks ? * inhibits AMP synthesis along with its guanine inhibition
When must 6-Mercaptopurine dose be lowered ? * when using allopurinol concurrently bc it inhibits xanthine oxidase, which breaks down 6-Merc... --> higher toxicities
Side effects/toxicities of Purine Analogs ? * BMD , Hyperuricemia , and Hepatotoxicity
Anti-metabolite -- Fludarabine use ? * CLL
Fludarabine MOA ? * Inhibits DNA synthesis (deoxyadenosine analog) --- by DNA polymerase, DNA primase, DNA ligase
Fludarabine SEs ? * black box for -- Autoimmune effects , Bone marrow suppression, Neurotoxicity..... * also see Progressive multifocal leukoencephalopathy -- usually fatal ...... * Tumor lysis syndrome
Antimetabolites - Summary ? * cell cycle dependant (needs cells to divide to work)
Antimitotic Drugs -- Vincristine and Vinblastine MOA ? * Binds to beta-tubulin --> inhibits microtubule polymerization
Vincristine uses ? * Leukemias, lymphomas (non-Hodgkin’s ) -- Treatment of choice to induce remissions in lymphocytic leukemia ..... * Hodgkin’s disease ..... * Wilms’ tumor..... * neuroblastoma
Vincristine SEs ? * Neurological toxicity (dose-limiting) .... * FATAL if given intrathecally
Vinblastine uses ? * Hodgkin's and non-Hodgkin's lymphoma ...... * Testicular cancer; breast cancer; Kaposi sarcoma
Vinblastine SEs ? * Myelosuppression --- dose limiting BMD ( vinBlastine ) ...... * no neuro
Antibiotics - doxorubicin, daunorubicin , idarubicin MOA ? * Intercalates into DNA ---> blocks DNA and RNA synthesis ..... * Inhibits topoisomerase II leads to strand breaks and apoptosis ...... * Free radical formation b/c powerful iron chelator (sponge)
Anthracycline that is most broad spectrum and the least ? * Most = Doxorubicin ..... * Least = Idarubicin (AML only)
Anthracycline SEs ? * BMD and Cardiotoxicity (ruby red for heart)
Enzymes - L-Asparaginase use and MOA? * Standard agent for treating lymphocytic leukemia including ALL .... * Hydrolyzes circulating L-asparagine needed for cells (starves them)
L-Asparaginase Side Effects ? * Anaphylaxis and serious allergic reactions ..... * Coag issues .... * Pancreatitis ..... * Azotemia
Retinoids - ATRA use and MOA ? * Use: acute promyelocytic leukemia (APL).... * MOA: provides homeostasis back to AML cells
ATRA SEs ? * Black Box: APL differentiation syndrome and Leukocytosis ..... * abnormal LFTs and hypertriglyc/cholesterolemia
Glucocorticoids - Prednisone and Dexamethasone uses ? * Suppresses lymphocyte proliferation
Targeted agents - Antibodies -- Rituximab use and MOA ? * Use: CD20-pos issues ...... * MOA: monoclonal antibody directed against the CD20 antigen on B-lymphocytes
Rituximab SEs ? * Black Box: HBV Reactivation (so get HepB tested), infusion-related reactions
Tyrosine kinase inhibitor - Imatinib use and MOA ? * USE: CML .... * MOA: Inhibits Bcr-Abl tyrosine kinase --> signal transduction inhibition
Imatinib SEs ? * fluid retention/edema , CV HF/LVD ,
Tyrosine kinase inhibitor - Dasatinib MOA ? * Inhibit both Bcr-Abl and Src kinases --- HIGHLY more potent on BCR than Imatinib, and good against BCR mutations.... *
Dasatinib SEs ? * QT prolongation --- Pulmonary arterial hypertension (PAH)
Histone deacetylase (HDAC) inhibitors --- Vorinostat Use and MOA ? * Use: Cutaneous T-cell lymphoma ...... * MOA: Inhibits histone deacetylase (HDAC) ---> remove acetyl groups --> Alters/Shuts Down transcription factors ….. Leads to cell cycle arrest
Vorinostat SEs ? * Hyperglycemia ---- QTc prolongation --- Thromboembolism --- Myelosuppresion --> thrombocytopenia and anemia
Proteasome inhibitors - Bortezomib Use and MOA ? * Use: multiple myeloma ...... * Reversibly inhibits 26S proteasome -- disrupts various cell signaling pathways - (ex. inhibits nuclear factor (NF)-kappaB)
Created by: thamrick800