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
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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. **
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