Cancer Chemotherapy

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what is a CCNS drug

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acts on tumor cells when they are traversing the cell cycle and when they are resting

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CCS drug

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acts tumor cells when they are traversing cell cycle and NOT when they are in G0 phagse

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Log-kill hypothesis

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concept used to mean that anticancer drugs kills a fixed proportion of a tumor cell poulation and not a fixed number of cells; a 1-log kill will decrease a tumor cell population by one order of magnitude (ie - 90% of cells will be eradicated)

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What are the mechanisms of resistance

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DNA repair
Formation of trapping agents - seen w/ bleomycin, cisplatin, and anthracyclines
Changes in target enzymes
Decreased activation of prodrugs
Inactivation of anticancer drugs
Decreased Drug accumulation - invovles increased expression of normal gene for a cell surface glycoprotein

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Alkylating Agents

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nitrogen mustards - Chlorambucil, cyclophosphamide, Mechlorethamine
Nitrosureas (Carmustine, Lomustine)
Alkylsulfonates - busulfan
Cisplatin, Dacarbazine, Procabazine act as partial alklyaters

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Cyclophosphamide

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needs P450 transformation for antitumor activity- acrolein is breakdown product; Non-hodgkins lymphoma, Breast and OVarian, and Neuroblastoma
Hemorrahgic cystitsi from acrolein may be decreased by hydration and use of Mesna

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Mechlorethamine

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spontaneously converts to ractive cytotoxic product; best known in use for Hodgkins; marked vesicant actions

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Cisplatin and Carboplatin

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Cis is used IV and widely distributed; commonly used for Testicular and for Bladder, LUng, and OVary cancer (Carbo is similar); Carbo is less nephrotoxic and less likely to cause hearing loss and tinnitus but is more myelosuppressive

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Procarbazine

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forms hydrogen peroxide which generates free radicals that cuase DNA strand scission; orally active and penetrates well; used primarily in Hodgkins; drug is leukemogenic

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Busulfan

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sometimes used in CML, causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation

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Carmustine (BCNU) and Lomustine (CCNU)

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highly lipid-solube used as adjuncts in managment of brain tumors

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Dacarbazine

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used in regimens for Hodgkins - causes alopecia, skin rash, GI, myelosuppression, phototox and flu-like

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Antimetabolites

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folic acid antagonists - methotrexate
pruine antagonists - mercaptopurine, thioguanine
pyrmidines antagos - fluoruracil, cytarabine
CCS drugs acting primarily in S phase

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Methotrexate

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substrate for and inhibitor of dihydrofolate reducaste leads to decrease in thymidylate, purine nucleotides and amino acid syntheis; oral and IV distributes widely except CNS; hydration is needed to prevent renal cystals; effective in Choriocarncionma, acute leukemias, NH and Cutaneous T-cell lymphonmas and Breast; also used in rheumatoid arhtirstis psoriasis and ectopic pregnancy; Leucovorin rescue - reduce toxic effects on normals cell

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Mercaptopurine and Thioguanine

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activated by hypoxanthine-guanine phosphoriboxyltransferases to toxic nucleotides that inhibit sevel enzymes in purine metabolism; resistnt tumor cells had decrease HGPRTase activity; low oral; 6-MP breakdown is inhibited by allopurinol; used mainly in acute and chronic myelocytic leukemias

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Cytarabine

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activated by kinases to AraCTP an inhibitor of DNA polymerases; most specific for S phase of tumor cell out of all antimetabolites; used parenterally and w/ slow IV infusion; most important component in regimens for ACUTE LEUKEMIAS; GI suppresion and myelosuprresion

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Fluorouracil

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converted to 5-FdUMP which inhibits thymidylate synthase and leads to thymineless death of cells; used in BLADDER, BREAST, COLON, HEAD AND NECK, LIVER, AND OVARIAN CANCERS - can be used topically for keratoses and superficial basal carcinoma

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Plant Alkaloids

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CCS drugs - most important are vinca alkaloids (vinblastine and vincristine), the podophylootoxins (etoposide, teniposide) and taxanes (paclitaxel, docetaxel)

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Vinblastine and Vincristine

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block formation of mitotic spindle by preventing assembly of tubulin dimers into microtubules - act primarily in M phase; both given parenterally; Vincristine --> ACUTE LEUKEMIAS, LYPMHOMAS, WILMS TUMOR, AND CHORIOCARCINOMA; Vinblastine --> lYMPHOMAMAS, NEUROBLASTOMA, TESTE, KAPOSI
vincristine does not cause myelosuprresion but has neurotoxic actions and may cause arelexia

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Etoposide and Teniposide

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Etoposide increases degradation of DNA and inhibits mitochondrial electron transport - most active in late S and early G2 stages, well absorbed after oral and well distribuited; used in SMALL CELL LUNG, PROSTATE, AND TESTE

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Paclitaxel and Docetaxel

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interfere w/ mitotic spindle; act differently from vinca alkaloids in that they prevent tubulin dissambley vs tubulin assempbly; both given IV; used in ADVANCED BREAST AND OVARIAN
Pacli causes neutropenia, thrombocytopenia, peripheral neruo
Docetaxel causes neurotox and bone marrow depression

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Antibiotics

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end in Icin or Mycin

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Doxorubicin and Daunorubin

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anthracyclines intercalate between base pairs, inhibit topoisomerase II, and generate free radicls - block syntheiss of RNA and DNA and cause DNA strand scission - they are CCNS drugs; must be given IV, cause red urine
DOXO used in HODGKINS, MYELOMAS, SARCOMAS, AND BREAST, ENDOMETRAIL, LUNG, OVARIAN AND THYROID; main tx of Daunorubinin is in tx oF ACUTE LEUKEMIAS, Idarubicin (newer) approved for Tx of AML; Dexrazoxane - inhibiotr or iron-mediated free radical generation may protect against cardiotoxicity

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Bleomycin

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mixture of glycopeptides that generates free radicals which bind to DNA, cause breaks and inhibit DNA synthesis; CCS drugs active in G2; must be given parenterally; inactivated by tissue aminopeptidases; component of drug regimens in HODGKINS and TESTICULAR and also used for treament of lyumphomas and squamous cell - tox to pulmonary (fibrosis); hypersensitivity reactions are common as are mucocutaneous

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Dactinomycin

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CCNS drugs that binds to dsDNA and inhibits DNA-depenedent RNA syntheis - must be given parenterally - used in MELANOMA AND WILMS

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Mitomycin

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CCNS drugs that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA - given IV against hypoxic tumor cells and used in combo in regimens for adenocarcinomas of cevix, stomach, pancreas, and lung

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Hormonal Anticancer Agents

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Glucocorticoids - Predinsone
Sex Hormone Antagonists - Tamoxifen, Toremifene, Flutamide
GRH Analogs - Leuprolide, Goserelin, Nafarelin
Aromatase Inhibiors - Anastozole

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Glucocorticoids

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Prednisone - most commonly used in chemo

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Sex Hormone Antagonists

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Tamoxifen - selective estrogen recper modulator blocks binding of estrogen to estrogen-sensitive cancer cells in breast tissue
Toremifine used in advanced breast cancer
Flutamide adnrogen receptor used in Prostatic carcioma - adverse effects include gynecomastia, hot flushes and hepatic dysfunction

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Gonadotropin Releasing HOrmone Analogs

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Leuprolide, Goserelin, Nafarelin effective in Prostatic carcinoma - inhibit LH release and FSH

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Aromatase INhibitors

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Anastrozole and Letrozole inhibit aromatase - enzyme that catalyzes the conversion of Androstenedione to Estrone - both used in advanced breast cancer

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tAsparaginase

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enzyme that deplese serum asparine used in treatment of T-cell auxotrophic cancers (leukemia and lymphoomas) that require asparine for growth - given IV and may cause hypersensitivty

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Imatinib

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selective anticancer drugs inhibits tyrosine kinase acitivate of protein product of Bcr-Abl ocogene that is expressed in CML - aslo effective in GI stromal tumors that express c-kit tyrosine kinase

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Interferons

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engoenous glycoproteins w/ antineoplastic, immunosuprressive and antiviral actions;
Alpha effective against hairly cell leukemia, early stages of CML, and T-cell lymphomas

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Monoclonal Antibodies

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Rituximab is monoclonal antibody to surface protein in NHL cells - currently used w/ convnentiol anticancer drugs in low-grade lymphomas
Trastuzumab is monoclonal antibody to surface protein in Breast cancers that overexpress HER2 preotin - may cause cardiac dysfunction leading to CHF

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Strategies in Cancer CHemo

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Combo therapy - each drug should be active when used alone against particular cancer
Drugs should have different mechanisms of action
Cross-resistance between drugs should be minimal
Drugs should have different tox effects

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Pulse Therapy

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intermittent treatment w/ very high doses of anticancer drugs - every 3-4 weeks allows for max effects on neoplastic cells w/ recovery in between

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Recruitment

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Recruitment involves initial use of CCNS drugs to achive good log kill which results in recruitment into cell division into G0 phase w/ subsdquent administeration of CCS drugs that is active against dividing cells;

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Synchrony

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Using a vinca alkaloid to hold cells in M phase and then subsequent tx w/ CCS drug (such as S phase specific cytarabine)

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Rescue Therapy

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Leucovorin - rescues normal cells from methotrexate damge
Mesna traps acoliein and reduces hemorrhagic cystitis
Dexrazoxane inhibits free radicals and may protect against cardiotox of anthracyclines (doxorubicin)

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ALL

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Induction: VINCRISTINE PLUS PREDNISONE
Maintenace: MERCAPTOPURINE METHOTREXATE AND CYCLOPHOSPHAMIDE

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AML

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Cytarabine and Daunorubicine or Idarubicin

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BREAST

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Cyclophospha and doxorubicin or hormonal therapy w/ tamoxifen or aromatase inhibitor (anastrozole)

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CML

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Imatinib, busulfan, or interferon

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Colon

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Flurocuracil, leucovorin, irinotecan

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Hodgkins

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ABVD regimen, doxorubin plus bleomycin plus vincristine plus dacarbaizine

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NHL

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clycophosphamide, doxorubine vincristine, prednison

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Ovarian

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Paclitael and Cisplatin or Carboplatin

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Prostate

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Leuprolie and Flutamide

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Lung

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Cisplatin plus Paclitaxel or Docetaxel

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Testicular

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PEB Regimen: Cisplatin (Platinol), Etoposide, Bleomycin