Antimetabolites Chemotherapy Drugs PDF

Antimetabolites Antimetabolites Chemotherapy drugs used to treat malignancy...

Antimetabolites Antimetabolites Chemotherapy drugs used to treat malignancy Block formation of components of DNA Cell cycle specific Toxic effects in S phase of cell cycle Antimetabolites Jason Ryan, MD, MPH Antimetabolites Nitrogenous Bases Pyrimidines Cytarabine Cladribine Methotrexate 5-fluorouracil Azathioprine Cytosine Thymine Uracil 6-mercaptopurine Purines 6-thioguanine Hydroxyurea Adenine Guanine Nucleotides Deoxyribonucleotides Pyrimidines Cytidine Thymidine Uridine ADP Ribonucleotide Reductase dADP Purines GDP dGDP Adenosine Guanosine 120 Common Side Effects Megaloblastic Anemia Drugs target rapidly dividing cells (DNA synthesis) ne i ( Hct) Bone marrow precursors cells: rapidly dividing rge B (↑ ) Myelosuppression Hypersegmented neutrophils Megaloblastic anemia Commonly caused by defective DNA production Thrombocytopenia B12/Folate deficiency Leukopenia Chemotherapy drugs (MTX, 5-FU, hydroxyurea) Absolute neutrophil count (ANC) Less than 500 cells/µL = neutropenia High risk of infections Wikipedia/Public Domain Cytarabine Cytarabine Ara-C or cytosine arabinoside Ara-C or cytosine arabinoside Pyrimidine analog Only effective in leukemia and lymphomas Mimics cytidine Adverse effects Inhibits DNA polymerase Myelosuppression Nausea/vomiting High doses: Neurotoxicity Peripheral neuropathy, confusion, cerebellar ataxia H Ara-C dCytidine Cladribine Methotrexate Purine analog Mimics of folate Mimics adenosine Inhibits dihydrofolate reductase Highly toxic to lymphocytes Blocks synthesis of tetrahydrofolate Drug of choice in hairy cell leukemia Required for DNA, RNA, some proteins Main adverse effect is myelosuppression Blocks synthesis thymidine (dTMP) Adenosine Cladribine Folate Methotrexate 121 Thymidine Methotrexate Clinical Uses Thymidylate Oral or intravenous Synthase Many malignancies Solid tumors dUridine-MP Thymidine-MP Leukemia/Lymphomas Immunosuppression Autoimmune diseases DHF Folate “Steroid sparing” agents N5, N10 Tetrahydrofolate Used to wean/eliminate need for long-term steroid use Pregnancy abortion Dihydrofolate Ectopic/tubal pregnancies THF Reductase Methotrexate Methotrexate Side Effects Side Effects Myelosuppression Mucositis (mouth soreness) More common with high doses Occurs with many chemo agents Reversible with leucovorin (folinic acid) Common with methotrexate Converted to THF GI epithelial cell damage Does not require dihydrofolate reductase Loss of mucosal integrity → pain, bacterial growth “Leucovorin rescue” Abnormal LFTs, GI upset Methotrexate 5-Fluorouracil Side Effects 5-FU Rarely causes methotrexate-induced lung injury Mimics uracil (pyrimidine) Fluorouracil Uracil Often after week/months of low-dose therapy Converted to 5-FdUMP (abnormal dUMP) Usually a hypersensitivity reaction Inhibition thymidylate synthase Lymphocytes, eosinophils Blocks dTMP synthesis (“thymineless death”) Can progress to pulmonary fibrosis Usually resolves on discontinuation of drug Effects n n by leucovorin 122  5-Fluorouracil 6-Mercaptopurine 5-FU Commonly used in colorectal cancer Fluorouracil Mimics hypoxanthine/guanine (purines) Other solid tumors: breast, pancreas Added to PRPP by HGPRT → Thioinosinic acid Topical therapy for basal cell skin cancer Inhibits multiple steps in purine salvage Adverse effects P P G P Myelosuppression Nausea/vomiting/diarrhea Mucositis Cerebellar ataxia and encephalopathy (rare) Coronary vasospasm Hypoxanthine 6-MP Guanine 6-Mercaptopurine Azathioprine GMP AMP Pro-drug Converted by the body to 6-MP 6-MP Guanine Hypoxanthine HGPRT Inosine monophosphate Hypoxanthine-Guanine (IMP) phosphoribosyltransferase PRPP Azathioprine 6-MP Purine Salvage Pathway Azathioprine/6-MP Azathioprine/6-MP Clinical Uses Adverse Effects Immunosuppression Myelosuppression Steroid sparing agents Abnormal LFTs Inflammatory bowel disease Anorexia/nausea/vomiting Solid organ transplant Autoimmune diseases 123 Xanthine Oxidase Azathioprine/6-MP Purine metabolism enzyme Also metabolized by xanthine oxidase Converts xanthine into uric acid Converts 6-MP to inactive metabolite Inhibited by allopurinol and febuxostat (gout) Caution with allopurinol/febuxostat Allopurinol Febuxostat Xanthine Xanthine Oxidase Oxidase 6-MP 6-thiouric acid Xanthine Azathioprine Uric Acid (inactive) 6-Thioguanine Hydroxyurea Also mimics hypoxanthine/guanine (purines) Inhibits ribonucleotide reductase Similar mechanism to 6-MP Blocks formation of deoxynucleotides P P G P Good oral bioavailability – can be used PO Main adverse effect is myelosuppression Guanine 6-TG Hydroxyurea Antimetabolites Rarely used for malignancy Used for polycythemia vera, essential thrombocytosis Used in sickle cell anemia Increases fetal hemoglobin levels (mechanism unclear) 124  Alkylating Agents Alkyl Groups Molecular groups with formula: CnH2n+1 Methyl group: -CH3 Ethyl group: -CH2CH3 Propyl group: -CH2CH2CH3 Alkylating Agents Jason Ryan, MD, MPH Alkylating Agents Alkylating Agents Add alkyl groups to nucleotide bases Most commonly N7 nitrogen of guanine DNA strands cross link Inhibit DNA replication and cause DNA damage Cell cycle non-specific Guanosine Myeloid Neoplasms Alkylating Agents Therapy-related myeloid neoplasms or t-MN Caused by exposure to DNA-damaging agents Nitrogen mustards Occur many years after exposure Nitrosoureas Acute myeloid leukemia (t-AML) Busulfan Myelodysplastic syndrome (t-MDS) Dacarbazine Alkylating agents are common cause Also topoisomerase II inhibitors or radiation 125  Nitrogen Mustards Nitrogen Mustards Alkylating Agents Alkylating Agents Alkylating agents similar to mustard gas Contain nitrogen and two chlorine atoms Mechlorethamine Cyclophosphamide R Melphalan Chlorambucil Ifosfamide Cyclophosphamide Cyclophosphamide Intravenous or oral forms Prodrug: Requires bioactivation by liver Good bioavailability when given orally Converted to phosphoramide mustard Powerful immunosuppressant Metabolized by liver P450 system Used in vasculitis, glomerulonephritis (oral) Solid tumors, lymphomas, leukemia Cyclophosphamide Wikipedia/Public Domain Cyclophosphamide Cyclophosphamide Side Effects Myelosuppression Mesna B Hct Plt Liver Hemorrhagic cystitis P450 4-Hydroxy Tissues Cyclophosphamide Aldophosphamide Acrolein metabolite toxic to bladder cyclophosphamide Hematuria +/- dysuria Lower risk with hydration and mesna Mesna: sodium 2-mercaptoethane sulfonate Acrolein Phosphoramide Mustard Mesna binds and inactivates acrolein in the urine (Cytotoxic) 126 Cyclophosphamide Ifosfamide Side Effects SIADH Isomer of cyclophosphamide Ifosfamide Drug has antidiuretic affects Used in germ cell cancer and sarcomas Usually occurs with IV dosing for chemotherapy May also cause hemorrhagic cystitis Hyponatremia; possible seizures Holly Fischer/Wikipedia Compounded by IVF Complex mechanism: More ADH release, less renal response Ifosfamide Nitrosoureas Special side effect: nephrotoxicity Ifosfamide Toxic to proximal tubular cells May cause Fanconi syndrome Polyuria Carmustine Lomustine Electrolyte losses: Hypokalemia, hypophosphatemia bis-chloroethylnitrosourea chloroethylnitrosourea BCNU CCNU Metabolic acidosis (loss of bicarb in urine) Special side effect: encephalopathy 10-30% of patients Streptozotocin Semustine Nitrosoureas Nitrosoureas Toxicity Bioactivated in liver Myelosuppression Highly lipid soluble → cross blood-brain barrier Rarely leads to pulmonary fibrosis Used for brain tumors (glioblastoma multiforme) Rarely chronic interstitial nephritis (renal failure) Encephalopathy and seizures Very high dosages (BCNU for bone marrow transplant) Wikipedia/Public Domain 127 Busulfan Busulfan Toxicity Myeloablation Myelosuppression Single, high-dose of Busulfan Skin hyperpigmentation Results in severe pancytopenia (bone marrow ablation) Also occurs with other chemotherapy (Bleomycin) Preparation for stem cell transplant Seizures (high dosages) Chronic myeloid leukemia (CML) Busulfan Dacarbazine Toxicity Pulmonary toxicity Part of ABVD protocol for Hodgkin lymphoma Cough, dyspnea Adriamycin (doxorubicin) - cytotoxic antibiotics Can progress to pulmonary fibrosis Bleomycin - cytotoxic antibiotics Ground glass opacities Vinblastine – microtubule inhibitor Restrictive PFTs Dacarbazine – alkylating agent Reduced DLCO Procarbazine Part of MOPP protocol for Hodgkin lymphoma Mechlorethamine – Mustard agent Oncovin (Vincristine) – Microtubule drug Procarbazine Prednisone 128  Antitumor Antibiotics Antitumor Antibiotics Drugs derived from Streptomyces bacterial strains Anthracyclines Antitumor Dactinomycin Bleomycin Antibiotics Jason Ryan, MD, MPH Anthracyclines Anthracyclines Key drugs: daunorubicin and doxorubicin Multiple toxic mechanisms Others: idarubicin, epirubicin, mitoxantrone Inhibition of topoisomerase II → DNA breaks Intercalation of DNA → blocks synthesis of DNA/RNA Generation of free radicals Cell cycle non-specific Daunorubicin Doxorubicin (Adriamycin) Topoisomerase II DNA Intercalation Cuts both strands of DNA helix then reseals Binds to DNA Relieves tangles and supercoils Inserts between base pairs Anthracycline inhibition → breaks with no resealing Inhibits replication/transcription Result: DNA damage Topoisomerases Wikipedia/Public Domain 129 Free Radicals Anthracyclines Clinical Uses NADPH Semiquinone Quinone Doxorubicin (Adriamycin) O· Widely used anticancer drug Breast cancer Many solid tumors Childhood cancers: neuroblastoma, Ewing’s, osteosarcoma Leukemia/lymphoma Fe2+ OH· H2O2 O2· O2 DNA Oxidative Damage Anthracyclines Anthracyclines Cardiotoxicity Cardiotoxicity Rarely seen with lower total dosages Free radical damage to myocytes → necrosis Dexrazoxane Can present with dyspnea, fatigue, edema Iron chelating agent Limits anthracycline-induced cardiotoxicity Screening: echocardiogram after infusions Dactinomycin Bleomycin Actinomycin D Several mechanisms Binds to DNA Intercalates in DNA Free radical formation (oxygen, iron) Inhibits RNA synthesis (transcription) Single and double strand breaks Double strand breaks Cell cycle-specific drug: accumulates in G2 phase Childhood cancers Neuroblastoma, Ewing’s sarcoma, osteosarcoma Major adverse effect: myelosuppression Zephyris /Wikipedia 130 Bleomycin Bleomycin Clinical Uses Toxicity Lymphomas Inactivated by enzyme bleomycin hydrolase Germ cell tumors Lower enzyme activity in skin and lungs Head and neck cancer Skin toxicity Squamous cell cancer of skin Many skin changes described Also seen with other chemotherapy drugs (Busulfan) Cancers of cervix and vulva “Flagellate erythema”: Red/dark streaks on skin Bleomycin Pulmonary Toxicity Dose-limiting adverse effect Usually presents as pneumonitis Cough, dyspnea, crackles Infiltrates on chest X-ray Risk factors Older patients (>70) Prior pulmonary disease 131  Microtubule Inhibitors Microtubules Polymers of and tubulin Can grow/collapse Microtubule Flagella, cilia, cellular transport (axons) Inhibitors Jason Ryan, MD, MPH Thomas Splettstoesser (www.scistyle.com) Mitosis Mitosis Metaphase Part of cell cycle Chromosomes line up on Separation of chromosomes for cell division metaphase plate Depends heavily on microtubules (mitotic spindle) Followed by cytokinesis: cell divides Ali Zifan/Wikipedia Lordjuppiter /Wikipedia Mitosis Cell Cycle Anaphase Chromosomes separate M Phase Mitosis G2 Phase Growth G1 Phase Growth S Phase DNA Synthesis Ali Zifan/Wikipedia Zephyris /Wikipedia 132 Microtubule Inhibitors Vocabulary Taxols Alkaloids Vinca alkaloids Naturally occurring substances Nitrogen-containing bases Usually derived from plants or trees Nicotine (Tobacco) Morphine (Opium) Taxols Taxols Paclitaxel, Docetaxel Paclitaxel, Docetaxel Alkaloids from yew trees Bind beta tubulin Mitotic spindle poisons Tumor resistance: Bind microtubules Alterations to beta-tubulin Increased P-glycoprotein Enhance tubulin polymerization Microtubules cannot break down P-glycoprotein: multidrug resistance protein Pumps foreign substances out of cells Blocks cell cycle at metaphase/anaphase transition Resistance of cancer cells to many chemotherapy agents Anaphase cannot occur Taxols Taxols Clinical Use Toxicity Solid tumors Hypersensitivity reactions (up to 30% patients) Ovarian and breast cancer Dyspnea/wheezing Non-small cell and small cell lung cancer Urticaria Head and neck cancers Hypotension Prostate and bladder cancer Premedication often used for prevention Glucocorticoids and antihistamines Nabpaclitaxel (Abraxane) Albumin-bound paclitaxel Lower risk hypersensitivity reactions Premedication not required James Heilman, MD 133 Taxols Vinca Alkaloids Toxicity Vincristine, vinblastine Myelosuppression Derived from periwinkle plant ( c rose ) Neuropathy Bind -tubulin Sensory nerves Inhibit polymerization Usually burning paresthesias of hands/feet Prevent spindle formation Mitotic arrest in metaphase Vinca Alkaloids Vinca Alkaloids Clinical Uses Toxicity Breast cancer Myelosuppression Germ cell cancer SIADH (rare) Lymphomas Vincristine: Neurotoxicity ABVD Protocol (Hodgkin lymphoma) Dose-limiting toxicity Adriamycin (doxorubicin) - cytotoxic antibiotics Loss of axonal transport Bleomycin - cytotoxic antibiotics Sensory and motor Vinblastine Paresthesias/pain in fingers and feet Dacarbazine – alkylating agent Distal weakness 134  DNA Drugs DNA Drugs Antitumor Antibiotics Alkylating agents Platinum agents Topoisomerase I and II inhibitors DNA Drugs Jason Ryan, MD, MPH Platinum Agents Platinum Agents Cisplatin, carboplatin, oxaliplatin Clinical Uses Cross link DNA similar to alkylating agents Solid tumors Most commonly at N7 nitrogen of guanine Non-small cell and small cell lung cancer “Alkylating like” drugs Esophageal and gastric cancer Cell cycle nonspecific (like alkylating agents) Head and neck cancers Testicular cancer Ovarian cancer Cisplatin Platinum Agents Platinum Agents Toxicity Nephrotoxicity All can cause neuropathy Main, dose-limiting side effect of cisplatin Usually a peripheral sensory neuropathy en pre en e i ne in r (↑B r) Pain, burning, tingling Prevented with IV fluids (normal saline) Often in feet or hands Increase urine output (cause diuresis) May also cause ototoxicity (hearing loss) Amifostine: Free radical scavenger Used in ovarian cancer with repeated cisplatin doses GI distress (nausea/vomiting) up to 90% patients Carboplatin: less renal toxicity Amifostine Pixabay/Public Domain 135 Topoisomerases Topoisomerases Relieve tangles and supercoils in DNA Topoisomerase I Cuts strands of DNA helix then reseal Breaks single strands of DNA then reseals Chemotherapy inhibition → breaks with no resealing Topoisomerase II Breaks double strands of DNA then reseals Result: DNA damage Affect S/G2 phase (during/after DNA synthesis) Topoisomerases Topoisomerase I Inhibitors Topoisomerase I Inhibitors Irinotecan, topotecan Clinical Uses “Camptothecins” Irinotecan From Camptotheca (“happy tree”) tree in China Colon Cancer Topotecan Ovarian cancer Small cell lung cancer Geographer/Wikipedia Topoisomerase I Inhibitors Topoisomerase II Inhibitors Toxicity Etoposide, teniposide Myelosuppression Synthesized from Podophyllotoxins Severe diarrhea Derived from May apple plant ( o op y m Risk of volume depletion Elya/Wikipedia Wikipedia/Public Domain 136 Topoisomerase II Inhibitors Clinical Use Intravenous and oral Germ cell cancers Small cell and non-small cell lung cancer Lymphomas Main toxicity: Myelosuppression, nausea/vomiting 137