This site is 100% ad supported. Please add an exception to adblock for this site.

Cancer Chemotherapy


undefined, object
copy deck
what is a CCNS drug
acts on tumor cells when they are traversing the cell cycle and when they are resting
CCS drug
acts tumor cells when they are traversing cell cycle and NOT when they are in G0 phagse
Log-kill hypothesis
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)
What are the mechanisms of resistance
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
Alkylating Agents
nitrogen mustards - Chlorambucil, cyclophosphamide, Mechlorethamine
Nitrosureas (Carmustine, Lomustine)
Alkylsulfonates - busulfan
Cisplatin, Dacarbazine, Procabazine act as partial alklyaters
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
spontaneously converts to ractive cytotoxic product; best known in use for Hodgkins; marked vesicant actions
Cisplatin and Carboplatin
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
forms hydrogen peroxide which generates free radicals that cuase DNA strand scission; orally active and penetrates well; used primarily in Hodgkins; drug is leukemogenic
sometimes used in CML, causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation
Carmustine (BCNU) and Lomustine (CCNU)
highly lipid-solube used as adjuncts in managment of brain tumors
used in regimens for Hodgkins - causes alopecia, skin rash, GI, myelosuppression, phototox and flu-like
folic acid antagonists - methotrexate
pruine antagonists - mercaptopurine, thioguanine
pyrmidines antagos - fluoruracil, cytarabine
CCS drugs acting primarily in S phase
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
Mercaptopurine and Thioguanine
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
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
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
Plant Alkaloids
CCS drugs - most important are vinca alkaloids (vinblastine and vincristine), the podophylootoxins (etoposide, teniposide) and taxanes (paclitaxel, docetaxel)
Vinblastine and Vincristine
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
Etoposide and Teniposide
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
Paclitaxel and Docetaxel
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
end in Icin or Mycin
Doxorubicin and Daunorubin
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
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
CCNS drugs that binds to dsDNA and inhibits DNA-depenedent RNA syntheis - must be given parenterally - used in MELANOMA AND WILMS
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
Hormonal Anticancer Agents
Glucocorticoids - Predinsone
Sex Hormone Antagonists - Tamoxifen, Toremifene, Flutamide
GRH Analogs - Leuprolide, Goserelin, Nafarelin
Aromatase Inhibiors - Anastozole
Prednisone - most commonly used in chemo
Sex Hormone Antagonists
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
Gonadotropin Releasing HOrmone Analogs
Leuprolide, Goserelin, Nafarelin effective in Prostatic carcinoma - inhibit LH release and FSH
Aromatase INhibitors
Anastrozole and Letrozole inhibit aromatase - enzyme that catalyzes the conversion of Androstenedione to Estrone - both used in advanced breast cancer
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
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
engoenous glycoproteins w/ antineoplastic, immunosuprressive and antiviral actions;
Alpha effective against hairly cell leukemia, early stages of CML, and T-cell lymphomas
Monoclonal Antibodies
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
Strategies in Cancer CHemo
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
Pulse Therapy
intermittent treatment w/ very high doses of anticancer drugs - every 3-4 weeks allows for max effects on neoplastic cells w/ recovery in between
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;
Using a vinca alkaloid to hold cells in M phase and then subsequent tx w/ CCS drug (such as S phase specific cytarabine)
Rescue Therapy
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)
Cytarabine and Daunorubicine or Idarubicin
Cyclophospha and doxorubicin or hormonal therapy w/ tamoxifen or aromatase inhibitor (anastrozole)
Imatinib, busulfan, or interferon
Flurocuracil, leucovorin, irinotecan
ABVD regimen, doxorubin plus bleomycin plus vincristine plus dacarbaizine
clycophosphamide, doxorubine vincristine, prednison
Paclitael and Cisplatin or Carboplatin
Leuprolie and Flutamide
Cisplatin plus Paclitaxel or Docetaxel
PEB Regimen: Cisplatin (Platinol), Etoposide, Bleomycin

Deck Info