dd onco - midterm charts

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  • 8/8/2019 DD ONCO - Midterm Charts

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    Drug/Class MOA Combination of drugs used ADRsAll are IV

    VINCA ALKALOIDS - M PhaseVinblastine

    Vinorelbine

    cancer (+Taxol + Gem)

    TAXANES - M PhasePaclitaxel

    Docetaxel

    Mechanism of resistance

    tubulin binding microtubule assemblycells are frozen inmetaphase preventscell proliferation.

    multidrug resistance,Pgp, MRP and/or

    Hodgkins disease, and testicularcancer (+CDDP+BLM) (PVB )

    Neurological (loss of deeptendon reflexes, pain andmuscle weakness).

    Vincristine-Oncovin

    multidrug resistance,Pgp, MRP and/orBCRP.

    Hodgkins disease (MOPP), andacute leukemia (POMP)

    non-small cell lung cancer(+CDDP or +Gem) and breast

    A unique inhibitor of mitosis, it promotes

    rather than inhibitsmicrotubule formation. Itpromotes polymerizationand stabilization of thepolymer rather thandisassembly. Thus itshifts thedepolymerization polymerization process tofavor the formation of microtubules. The overlystable microtubulesformed arenonfunctional, andchromosomedesegregation does notoccur. This results indeath of the cells.

    multidrugresistance(MDR), Pgp,

    MRP7, beta-microtubule mutation.

    metastatic ovarian and breast,head and neck cancers, first line

    drug for NSCLC (+CDDP)

    * It is a radiation sensitizer

    Hypersensitivityreactions(due to the drug

    formulation not the drugitself) ,Neurotoxicity,cardio- and liver toxicity

    Same as Paclitaxel butstronger

    Breast and lung cancer afterfailure of prior chemotherapy.(Either single or combine withCDDP)

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    EPIPODOPHYLLOTOXINS - S and G2 Phase Thrombocytopenia, GI tox

    Etoposide Myelosuppression

    Teniposide Myelosuppression, NVD,hypersensitivity

    CAMPTOTHECIN (CPT) ANALOGS - S PhaseCamptothecin

    Irinotecan

    Topotecan

    Podophyllotoxin

    Form a complex withtopoisomerase II andDNA prevent resealingof the break thatnormally follows

    topoisomerase binding toDNA. The enzymeremains bound to thefree end of the brokenDNA strand, leading to anaccumulation of doublestranded DNAbreaks cell death

    MDR, Pgp, MRPs, TopoII mutation

    pediatric leukemia, small cellcarcinoma of the lung, testicularcancer, Non-Hodgkins disease.

    Phenobarb induces CYP450decresing theconcentration of thecancer drug

    small cell carcinoma of the lung(EP:+cisplatin ), testicular cancer(EB:+ bleomycin or EP: +cisplatinacute lymphoblastic leukemia inchildren, brain tumor metastasesfrom small cell carcinomas of thelung.

    Bind to and stabilizeDNA-Topo I cleavablecomplex causeirreversible double strandDNA break cell death.(the religation step isinhibited bycamptothecin, leading tothe accumulation of single-stranded breaks inDNA)

    Pgp, MRP, BCRP,TopoI mutation

    colorectal, ovarian, and small celllung cancer

    Myelosuppression,hemmorhagic cystitis

    advanced colorectal cancer, non-small cell lung cancer, gastric

    Myelosuppression,neutropenia, GI symptoms

    ovarian, small cell lung cancer,Metastatic brain cancer

    Myelosuppression,neutropenia, GI symptoms

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    ANTIBIOTICS-ACTINOMYCINS NON CELL CYCLE SPECIFICDactinomycin

    It is a radiation sensitizer

    Mitomycin

    adrenocarcinomasPlicamycin severe hemorrhaging

    It intercalates betweenthe base pairs of DNAand inhibits

    Topoisomerase II activity.It selectively inhibits the

    synthesis of DNA-dependent ribosomalRNA and mRNA)

    Unknown. Maybe DNArepair

    Wilms tumor (nephroblastoma) inchildren. It is curative (withcyclop. or oncovin) of choriocarcinoma after failure withMTX. Also used for inhibiting

    immunological responses (e.g.renal transplants)

    myelosuppression, andgastrointestinaldisturbances

    tissue injury may occur atthe injection site.

    It is activated byreduction to abifunctional alkylatingagents. More active inhypoxic areas.

    disseminated solid (hypoxic)tumors such as breast, gastric,pancreatic or colorectal

    highly GI disturbance andmarrow toxicity,pulmonary edema andfibrosis may occur

    Inhibit DNA-dependent

    RNA polymerase

    advanced embryonal tumors of

    testes. It has been largelyreplaced by new agents such asbleomycin and cisplatin

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    ANTIBIOTICS-ANTHRACYCLINE NON CELL CYCLE SPECIFICDaunorubicin acute lymphocytic leukemia

    Doxorubicin cardiac toxicity

    Idarubicin chronic myelogenousleukemia (CML)

    Epirubicin adjuv therapy of breast cancerMitoxantrone

    ANTIBIOTICS G2 and M Phase

    It intercalates intodouble-helix DNA & alsoinhibits the ligaseactivtity of

    Topoisomerase II

    multidrug resistance,Pgp, MRP and/orBCRP

    cardio toxicity (generateshydroxyl and superoxideradicals damage cellularmembrane), bone marrowdepression

    (ALL), and granulocytic leukemia(AGL)

    broad spectrum of tumors, acutelymphocytic leukemia (ALL),Hodgkins disease, Wilms tumor,neuroblastoma, ovarian cancer.FAM(5FU+Adriamycin+mitomycinfor colorectal cancer)

    cardio toxicity, and dose-limiting toxicity ismyelosuppression(especially leukopenia)

    multidrug resistance,Pgp,BCRP/ABCG2/MXR, Topoisomerase IImutation

    Hodgkins and non-Hodgkinslymphomas, acute leukemia,breast and prostate cancer

    myelosuppression,mucositis, less cardiactoxicity compared withdoxorubicin (ADM),because it has limited toproduce oxygen freeradicals.

    Bleomycin

    IM and IV

    Involves binding to theDNA following by singleor double strandcleavage. (A DNA-bleomycin-Ferrouscomplex appears toundergo oxidation tobleomycin-Ferric,liberated electrons reactwith oxygen to formsuperoxide or hydroxideradicals, which attack thephosphodiester bonds of

    DNA, resultin in strand

    experimental systemshave implicatedincreased levels of bleomycin hydrolase(or deaminase),glutathione-S-transferase, andpossibly increasedefflux of the drug.DNA repair also maycontribute.

    squamous cell carcinomas of thehead and neck, esophagus, skinand genitourinary tract. Combinetreatment of testicular cancerwith vinblastine and cisplatin(PVB) or cisplatin and etoposide(PEB).

    pulmonary fibrosis toxicity,skin &

    mucous toxicity, but verylittle marrow toxicity

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    Drug/class/ROA MOA Mechanism of resistance Combination therapy used ADR

    Cisplatin

    (Platin) Ovarian, bladder and lung carcinoma

    IVCarboplatin Similar to cisplatin(Platin)

    IVOxaliplatin Similar to cisplatin Gastric, colorectal

    (Platin) Non cell cycle phase specific

    IV

    breakage)

    Intrastrand crosslink affectDNA replication

    DNA repair activity,MRP2,MRP6,GSH

    PVB: cisplatin, vinblastine,bleomycin metastatic testicular cancer

    Renal tox(tubular necrosis), liver and nerve tox, hypersensitivityeffectsOnly the cis bis-chloro structure

    is active

    DNA repair activity, production of nucleophilicsubs such as GSH

    Advanced ovarian cancer, non-small celllung cancer

    Renal(< than cisplatin), BMsuppression

    DNA repair activity,

    production of nucleophilicsubs such as GSH

    Renal tox(< than

    cisplatin), peripheralneuropathy, nausea is wellcontrolled by 5-HT3 antagonists

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    Drug/class MOA Combination therapy used ADR

    NITROGEN MUSTARDSMethchlorethmine Potent vesicant

    IV

    -non cell cycle specific

    Breast cancer & immunosuppressant

    Melphalan L-phenylalanine analog

    PO

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    chlorambucil and phenyl aceticacid(metabolite) are both active

    - can cause secondary leukemia andsterility

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    AZIRIDINES

    Terithylenmelamine Hodgkins disease and lymphomas

    ALKYL SULFONATE

    AZINES &HYDRAZINES AKA TRIAZINESDacarbazine(DTIC)

    IV, IM

    Procarbazine Methylating agent, readily forms radicals

    Thiotepa

    IV & IC (intracavity)

    The aziridine rings open after protonation of the ring nitrogen leading to a reactivemolecule which alkylates DNA by formingDNA cross-links

    Bladder cancer, breast and ovarian cancer,immunosuppressant for BM transplant

    - myelosuppression, mucositis, BMtox, blood counts, CNS tox(crossesBBB)

    Activated by microsomal enzymes and is N-demethylated with release of formaldehyde

    -

    Busulfan

    PO

    chronic granulocytic leukemia and chronicmyelogenous leukemia

    - Myelosuppression,rare nvd

    - High dose pulmonary fibrosis,hepatic venooclusive disease andhyperuricemia

    methylating agent after metabolic activationin the liver

    DT: Dacarbazine,Tamoxifen malignantmelanoma

    - nv, myelosuppression, neurotoxicity

    resistance: s the repair activity of

    methylated guanine bases by guanine O 6 alkyltransferase

    MOPP: Mechlorethamine,Oncovin,Procarbazine,Prednisone - Hodgkinsdisease

    - leukopenia, TCP, neurotox,- inhibits P450- tox of barbiturates

    - MAOI avoid cheese

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    NITROSOUREAS

    Streptozocin Antibiotic SMF: Streptozocin,Mitomycin,5FU,

    IV

    Carmustine (BCNU)

    IV

    Alkylates DNA at the O6 guanine positionkilling cells in all phases of the cell cycle

    Brain tumors(crosses BBB) andgastrointestinal neoplasms

    - Myelosuppression

    - High dose hepatic venooclusivedisease, pulmonary fibrosis, renalfailure, secondary leukemia

    Lomustine (CCNU)

    PO

    Brain & colorectal tumors, hodgkinsdisease, lung cancer

    - nvd, myelosuppression

    Semustine

    PO

    Broad spectrum anticancer, Malignantmelanomas, colorectal cancer,

    - Toxicity is less than CCNU andBCNU, nvd & myelosuppression

    - nausea,renal and hepatic tox,hematological tox (< than CCNU)

    Malignant pancreatic islet cell tumors(survival rate by 1 yr)

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    Drug/Class/ROA MOA S Phase Mechanism of resistance Combination therapy used ADR PTERIDINES

    Methotrexate

    PO

    PYRROLOPYRIMIDINEPametrexed unknown malignant pleural mesothelioma

    Inhibition of DHFR leads to toxiceffects thru depletion of tetrahydrofolate cofactors that arerequired for purines and thymidylate

    synthesis

    1. Impaired transportMTX into cells,(reducedfolate carrier, RFC1)

    ALL POMP(6MP,vincristine,methotrexate,prednisone)

    Heparic fibrosis, cirrhosis, pneumonitis, GI tox

    Leucovorin- rescue agent- preventsthe lethal effect of MTX on normalcells,Trimetrexate folate antagonist

    2. Impaired polyglutamate formation(FPGS).

    Adj for breast cancer CMF(Cyclophosphamide,MTX,5FU)

    3. Increased DHFR activity.

    4. IncreasedThymidylate synthase

    activity.5. Overexpressed ABC(ATP-Binding Cassette)transporters for effluxingMTX from the cells(MRP1-5, BCRP). **

    Similar to folic acid. Inhibits 3enzymes used in purine and

    pyrimidine synthesisthymidylatesynthase (TS), dihydrofolate reductase(DHFR), and glycinamideribonucleotide formyltransferase

    Hematologic tox(dose limited)and GI tox, skin rash.

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    PYRIMIDINES5-FU chest pain, cardiogenic shock

    Fluorouracil Inhibit TS, which is an enzyme that Same as 5-FU

    IVCapecitabine Same as 5-FUPOProdrugCytarabine cholestatic jaundice

    Gemcitabine Not a cell cycle specific drug

    1. Loss or decreased activityof the enzymes necessary for activation of 5-FU ( such asTP)

    solid tumors such as colorectal(FAM: 5-FU+Adriamycin+Mitomycin), breast, ovarian,

    pancreatic carcinomas (CMF:C clo hos hamide+ MTX + 5FU

    2. Increased thymidylatesynthase activity.

    3. Overexpressed ABC (ATP-Binding Cassette) transportersfor effluxing 5-FU from thecells (MRP5,8)Prodrug is capecitabine

    Hepatic carcinoma treatment .converts 2 deoxyuridylic acid to

    thymidylic acid.

    Unknown but maybe similar to 5-FU

    metastatic breast cancer resistantto Taxol & Vincristine, colorectalcancer

    Reversible fertilityimpairment,hyperbilirubinemia.

    Require intracellular phosphorylation,AraCTP is its active metabolite,which is able to block DNA synthesiswith little effect on RNA/proteinsynthesis.

    Decreased deoxycytidinekinase activity (to produceAraCMP), Increased cytidinedeaminase activity (todegradate to Arauridine, anon-toxic agent), and MRP8 isa pump for AraCMP in our recent experiments

    Acute myelocyte leukemia.(AML) (it is the single mosteffective agent for induction of remission in this disease)

    IV(deamination inGI)

    Aactivated (by kinase) to deoxytriphosphate nucleotide, which is able

    first line regimen for patients withmetastatic pancreatic cancer and

    Myelosuppression, lighthepatic toxicity

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    non-sma ce ung cancer ; :cisplatin).

    prodrug

    IV

    Decreased deoxycytidinekinase activity, Increasedcytidine deaminase activity,and MRP7 is a pump for Gemcitabine in our recentexperiments

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    PURINESFludarabine Increase adenosine deaminase

    Same as 6-Mercaptopurine

    inhibits DNA polymerase, DNA primase, DNA ligase, andribonucleutide reductase incorporated into DNA & RNA inhibits DNA synthesis

    chronic lymphocytic leukemia andlow-grade lymphomas

    bone marrow depression andgastrointestinal effects; chillsand fever

    6-Mercaptopurine

    IV, PO

    Activation of drug by metabolism tonucleoside form & then

    phosphorylation. The activemetabolite tNMP thio urine

    1. Decreased nucleotidetransport carrier expression

    Acute leukemia in children.Improved survival for leukemia to~80% (POMP)

    Hepatotoxicity, leukopenia,thrombocytopenia and

    bleeding

    2. Increaseddegradation of the

    phosphate conjugate andMRP5 are able to effluxthe drugs from the cells

    6 Thioguanine

    IV, PO

    The active metabolite (6-thioguanosine monophosphat, 6-thioGMP) is incorporated intoRNA/DNA, where it inhibitsRNA/DNA syn.

    Acute granulocytic leukemia, can be used as an immunosuppressiveagent.

    BM deppression &gastrointestinal effects.Hepatotoxicity is less than 6-MP. No drug interaction withallopurinol.

    Cladaribine

    IV

    2-CdA is conversed to CdA-TP bydeoxycitidine kinase. CdA-TP

    produces DNA strand breaks (inhibitDNA repair enzymes such as nickaseand ligases)

    Not clear. BCRP is a pump to pump out 2-CdA

    Very effective in hairy cellleukemia.

    Not good for solid tumors.

    Myelosuppression, NVD andfever

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    MISCELLANEOUSPentostatin

    IV

    Pentostatin is a strong (irreversible)inhibitor of adenosine deaminase(ADA). Accumulation of adenosinecan block DNA synthesis byinhibiting ribonucleotide reductase,

    can also inhibit RNA synthesis, andits triphosphate derivative if incorporated into DNA.

    Not clear In clinical trials, it showed asynergistic effect on theactivity of Ara C.

    Leukemias. acute leukemia inchildren, hairy cell leukemia. Notgood for solid tumors.

    Myelosuppression,gastrointestinal disorders, skinrashes, and abnormal liver function.

    **RFC reduced folate carrier-RFC1FPGS - folypoly glutamate synthetaseFPGH - folypolyglutamate hydrolaseMTX enters the cells primarily via the RFC1, inside the cell, MTX is glutamylated by FPGS to MTX polyglutamates which can be converted back to theparental drug by FPGH. MTX is subject to efflux by MRPs1-5, where MTX-polyglutamates are not. Etoposide are substrates of MRP1-3 and may function as

    inhibitors of MTX efflux. MTX may inhibit MRP4-mediated efflux of nucleotide analogs. **