o A disease state characterized by abnormal hyperproliferation of cells Types of Tumors ANTICANCER DRUGS Cancer Benign Malignant Metastatic o Development of cancer or neoplasm Exposure to mutating influence Activation of cellular oncogene Dedifferentiation primary tumor Early tumor development Gompertzian growth Metastasis spread Secondary tumor o Distinction between cancer that produces a solid tumor and a disseminated cancer e g leukemia that is not localized Cell Cycle o Phases of Cell Cycle Go resting phase no cell division or DNA replication G1 presynthesis phase protein biosynthesis G2 post synthesis pre mitotic M mitotic phase second most sensitive part of cell cycle S synthesis of DNA most sensitive part of cell cycle Principles of Chemotherapy o Goal if possible to kill 99 of all tumor cells leave normal cells alone o To achieve goal usually requires combination therapy i e drugs to attack cells in multiple phases More effective against small tumors Combination therapy usually more effective than single therapy Surgery plus chemotherapy reduces primary burden and hits micro metastases o e g POMP Prednisone Oncovin vincristine Methotrexate Purinethiol mercaptopurine for acute lymphocytic leukemia ALL Limiting Toxicities o For each drug used to treat cancer there is usually a small group of toxicities that limit the maximum dose o Usually occur in cells that normally are rapidly dividing e g bone marrow hair follicles o Try to minimize overlapping toxicities when using multiple drugs o Some toxic reactions can be minimized by interventions e g Filgrastim Colony Stimulating Factor counteracts neutropenia Side effects Adverse reactions o Alopecia hair loss o Stomatitis inflammation of the mouth o Gastrointestinal problems o Bone marrow suppression BMS Leukopenia thrombocytopenia anemia e g 5 Fluorouracil o Cardiotoxicity Doxorubicin Other problems with Chemotherapy o Resistance some cancers are inherently resistant e g melanoma o Multidrug resistance MDR a gene product called P glycoprotein pump multiple drugs out of cells Found in all cells but increased in cancer cells o Anti cancer treatments can often cause other cancers later because Tx leaves behind damaged DNA CLASSES OF ANTICANCER ANTINEOPLASTIC AGENTS o Antimetabolites Target is S phase cycle specific You are responsible for prototypes marked Antifolates Methotrexate Trimetrexate Leucovorin rescue Nucleosides 5 Fluorouracil Mercaptopurine Adenosine arabinoside Ara A Cytarabine Ara C DNA Targets o Both cell cycle dependent and cycle independent drugs target DNA o Anti metabolites are similar to normal cell components needed for DNA synthesis o Antibiotics disrupt DNA function o Alkylating agents bind to DNA in both cycling and non cycling 5 Fluorouracil 5 FU cells rate Effects of 5 FU synthetase o Anti metabolite most effective against tumors with high growth o BMS GI effects stomatitis N V ulcers bleeding major toxicities o Works as a false metabolite to prevent DNA synthesis o 5 FU gets converted to act like thymidine and blocks thymidylate o Without thymidine DNA synthesis stops blocks S phase o Can be used with cisplatin levamisole or leucovorin o Usually given IV o WBC nadir 10 14 days later o Crosses blood brain barrier used in CNS o Metabolized in liver excreted by kidneys o Patient implications Monitor white blood cells closely Warn about mouth sores at 1 week blood in stool Avoid aspirin other anticoagulants Anti mitotic Agents o Plant derived products Vinca alkaloids from periwinkle Vincristine Oncovin Vinblastine o Paclitaxel Taxol from Pacific yew Prototypes Vinca Drugs o Block M phase leading to cell death Vincristine Oncovin o Used for acute lymphocytic leukemia others o Used only IV o Is a vesicant blisters use extravasation precautions o Neurological toxicities include numbness tingling in extremities o Severity of toxicity related to cumulative dose o Use caution with pre existing neurological problems o Contraindicated for Charcot Marie Tooth demyelinating syndrome o Liver damage may require lower doses o Constipation drug interactions with opiates Paclitaxel Taxol has opposite effect on tubulin than vincristine o Used to treat ovarian breast cancer used IV o 10 of patients have hypersensitivity to diluent predose with corticosteroid antihistamines to prevent anaphylaxis o BMS neurotoxicity are major limiting toxicities Topoisomerase Inhibitors o Topotecan Topoisomerase I inhibitor o Etoposide Topoisomerase II inhibitor o DNA needs to unwind in order to replicate or for making mRNA transcription o Topoisomerases are enzymes that break then re anneal DNA in order to allow it to unwind o Inhibiting topoisomerases leads to DNA breaks that are not repaired causing cell death o Topoisomerases come in two forms type 1 and 2 Type 1 cuts only one DNA strand but type 2 cuts both strands o Topoisomerase inhibitors interfere with S and G2 phases of the cell cycle Topotecan Topoisomerase 1 inhibitor o Blocks ability of topoisomerase 1 to repair nicks in DNA o Causes BMS and thrombocytopenia neutrophil count should be 1 5K cells mm3 and platelets should be 100K cell mm3 o Non hematological side effects include N V GI upset alopecia and fatigue o Avoid infections and cuts in patients Etoposide Topoisomerase II inhibitor o Causes BMS o Given IV can cause anaphylaxis when given rapidly requires slow administration o Inhibits DNA synthesis in S and G2 phases by preventing repair of DNA breaks by TopoII o Can cause radiation recall a rash in irradiated area o Is an irritant that can cause pain and inflammation along vein for IV o Can cause metallic taste suck candy during administration Alkylating Agents not cycle specific o Cell cycle nonspecific drugs are considered more toxic than cycle specific drugs o Nitrogen mustards Chlorambucil Leukeran Cyclophosphamide Cytoxan o Nitrosoureas Carmustine BCNu Lomustine CCNu o Other alkylator like drugs Bysulfan myleran Cisplatin platine Procarbazine Dacarbazine Cyclophosphamide Cytoxan o Activated by metabolism in the liver o Generates phosphoramide mustard and acrolein o Phosphoramide mustard attaches to DNA and kills cells o Used to treat a variety of cancers including breast cancer Burkitt s lymphoma o Also used on non cancer diseases involving rapid cell division such as intractable rheumatoid arthritis o Kills cells independent of cell cycle but leaves a high level of damaged DNA that can cause later cancers o Preferred route is PO crosses BBB o Limiting acute