Chemotherapy Flashcards

Question

Vinca alkaloid is a \_\_\_\_? What do you do if they extravasate?

Answer 1

Vesicant Aspirate drug out Warm compress Can inject warm saline Can inject hyaluronidase --\> Breaks down hyaluronic acid in soft tissue, allowing for dispersion of the extravasated drug

Answer 2

ELSPAR --\> Reduces hepatic clearance of vcr Methotrexate --\> Vinca alkaloids block efflux leading to increased intracellular accumulation Cytochrome P450 inhibitors --\> Increases toxicity of vinca alkaloids

Answer 3

Plant alkaloids from --\> Bark of pacific yew, Needles of European yew **Paclitaxel** - naturally occurring Vehicle = polyoxyethylated castor oil (Cremophor EL) **Docetaxel** - semi-synthetic Vehicle = polysorbate 80 (Tween 80)

Answer 4

Bind polymerized tubulin along length of MT -N-terminal of β-subunit At lower doses = inhibit dynamic instability and treadmilling At higher doses = inhibit MT disassembly Promote elongation --\> stabilizes the MT against disassembly and enhances polymerization Inhibits dynamic reorganization of MT network

Answer 5

Metaphase/anaphase junction MT disruption induces p53 and inhibitors of CDKs (ie p21/Waf-1) - cells arrest in G2/M - APOPTOSIS * Activation of proapoptotic molecules (Bax/Bad) * Inactivation of anti-apoptotic molecules (Bcl-2 and BclxL Mainly M-phase specific but can also block G0/G1-\> S

Answer 6

Disrupts interphase MTs and DNA synthesis in non-dividing cells Disrupt endothelial cells and inhibit angiogenesis Inhibits neutrophils, proliferation of lymphocytes and fibroblasts Induces expression of TNF-α (mediator of inflammation and apoptosis) Inhibits secretory functions Radiosensitizer

Answer 7

MDR (MDR1 and MDR2) Alteration in tubulin binding sites Decreased apoptosis d/t altered cell signaling

Answer 8

Metabolized by cytochrome p450 in the liver and excreted in the bile/feces – \<15% renal excretion – Decrease dose w/ hepatic disease Large volume of distribution • High clearance • Long half-life • Extensive protein binding

Answer 9

– High Pgp on enterocytes – Intestinal cytochrome p450 enzymes – Drug metabolized in the enterocyte -\> reduced amt of parent compound reaching circulation Cyclosporine - Can alter Pgp/cytochrome p450 function with certain drugs -\> increasing oral absorption

Answer 10

neutropenia (3-5 day nadir) Type I hypersensitivity (to carrier molecule), GI rare

Answer 11

–Cardiac • Transient asymptomatic bradycardia most common, other arrhythmias • Long-term tx -\> cardiac dysfunction Neurotoxicity -\> peripheral neuropathy (sensory) – Rarer effects * Hepatotoxicity/pancreatitis * Acute pneumonitis * Nail disorders

Answer 12

Edema and 3rd spacing (increased capillary permeability) Dermatologic - palmar-plantar erythrodysethsia Nail bed changes - brown coloring, ridging, loss of nail plate Neurotoxicity - paresthesia/numbness Conjunctivitis, excessive lacrimation (like Gina)

Answer 13

NITROGEN MUSTARDS • Mechlorethamine (Mustargen HCl) • Chlorambucil (Leukeran) • Melphalan (Alkeran) • Cyclophosphamide (Cytoxan) • Ifosfamide (Mitoxana) NITROSUREAS • CCNU/Lomustine (CeeNu) • BCNU/Carmustine (Carustine) • Busulfan (Myleran) \*\*Alkyl alkane sulfonate • Streptozotocin (Zanosar) \*\*Methylnitrosurea Other (ie Aziridines) • Thiotepa (Thioplex) METHYLATING AGENTS – Procarbazine (Matulane) – Dacarbazine (DTIC) – Temozolomide (Temodar)

Answer 14

Target DNA via alkylation of DNA base pairs * Bonding of alkyl groups (-CH2Cl) - generates highly reactive (+)-charged intermediates that react with electron rich nucleophilic groups Nitrogen mustards = N7 on guanine Nitrosureas = O6 methyl group on guanine Methylating agents = O6 methyl group on guanine

Answer 15

Lipid soluble - readily enter cells via passive diffusion Mustargen and Melphalan require active transport Form interstrand cross-linking of DNA - prevents cell replication and cells die by apoptosis Inhbits DNA, RNA, and protein synthesis Cell cycle non-specific

Answer 16

Bi-functional = contains TWO reactive groups * Can form cross-links (inter and intrastrand) * Prevents cell replication unless repaired * Prevents cell replication unless repaired * **Nitrogen mustards and BCNU, busulfan** Mono-functional = contains ONE reactive group * Cause SS breaks and DNA base damage * **CCNU and Methylating agents, streptozocin**

Answer 17

Alkylguanine O6-alkyl transferase (AGT) repair * Attack O6 methyl group of guanine -\> can pair with thymine resulting in G:C to A:T during DNA replication * Can be repaired by AGT (encoded by MGMT gene) Mismatch repair * Recognizes mismatch created by alkylation of DNA bases * Repeated attempts to repair O6-meG:T mismatch -\> after unsuccessful repair, get ss and ds breaks -\> cell death

Answer 18

DNA excision repair * BER – DNA glycosylases recognize single base lesions – Lesions excised and missing DNA segment is resynthesized by DNA polymerase, then DNA is re-ligated * NER – Excises bulky adducts and DNA crosslinks – Repairs DNA ds breaks Cross-link repair -\> combo of NER plus homologous recombination

Answer 19

Bi-functional, targets N-7 on guanine Parent drug -\> 4-OHCOP↔ aldophosphamide - Goes into cells and decomposes to phosphoramide mustard + acrolein OR Inactivated by aldehyde dehydrogenase to carboxyphosphamide 10% goes thru alternative pathway -\> forms neurotoxin chloracetylaldehyde Isomer of cyclophosphamide; Less affinity for cytochrome P450 enzymes; More inactivated by other pathways (such as dechlorethylation) • Why higher doses are needed causing different toxicity profile

Answer 20

Drug exposure to cyclophosphamide after IV significantly higher than PO – First past elimination through the liver No significant difference in exposure to 4- OHCP

Answer 21

Is hematopoietic stem cell (HSC) sparing * High levels of aldehyde dehydrogenase (ALDH) in HSCs – Converts cyclophosphamide to inactive form * ALDH -\> may play role in early differentiation of HSCs

Answer 22

**Dose-dependent nonlinear PK** – Significant delays in elimination at higher doses **Induces its own metabolism -** Significant shortening of elimination t1/2 for parent compound when administered on multiple consecutive days **Major site of clearance is liver** – Small % of drug eliminated in the urine

Answer 23

**DLT = Myelosuppression (cyclophosphamide \> ifosfamide)** Sterile hemorrhagic cystitis (ifosfamide \> cyclophosphamide) – Can administer MESNA (2-mercaptoethane sulfonate) – How dose MESNA work? • Conjugates with acrolein Teratogenic, carcinogenic Cardiotoxicity (high dose cyclophosphamide) SIADH (cyclophosphamide) Renal toxicity (ifosfamide) Neurotoxicity (ifosfamide) – D/t increased formation of chloroacetylaldehyde

Answer 24

Mustard gas Metabolized in plasma, excreted in urine

Answer 25

* **Decreased transport across cell membrane** – Mustargen and Melphalan require active transport into cells * **Increased glutathione or glutathione-S-transferase** – Free radical scavengers – Inactivate alkylating agents * **Increased detoxification of reactive intermediates** – Example -\> increased ALDH * **Enhanced DNA repair** – Increased AGT-mediated repair – MMR deficiency – Increased efficiency of BER/NER/repair of crosslinks * **Increased expression of AKT** – AKT activation ! inhibition of apoptosis via phosphorylation of proapoptotic molecules (Bax, Bad, Bim) * **Defects in cell cycle arrest/apoptosis** – Loss of p53 – Upregulation of antiapoptotic proteins (Bcl-2, Bcl-XL) – Upregulation of ATM/ATR

Answer 26

* **Decreasing glutathione or GST** – BSO, amifostine * **Decreasing AGT-mediated repair** – O6-benzyl guanine (OBG) * **Inhibition of BER** – Methoxyamine -\> binds AP site and prevents enzyme activation – PARP inhibitors - cause ss and ultimately ds breaks (PARP normally leads to recognition of AP site by enzymes) * **Inhibition of AKT/mTOR pathway** – Rapamycin (inhibits mTOR) – Wortmannin (inhibits AKT)

Answer 27

Cisplatin • Carboplatin • Oxaliplatin • Satraplatin

Answer 28

Planar structure with **four** attached chemical groups * Platinum (II) compounds (ie exist in the 2+ oxidation state) * Core structures are the same based on the cis configuration of Pt(II) * Analogs in cis configuration are clinically active (not trans)

Answer 29

Leaving group **Cisplatin** -\> Cl- atom * Serves same function as alkyl group * Prefers N7 position of guanine and adenine (similar to alkylating agents **Carboplatin** --\> cyclobutanedicarboxylate **Oxaliplatin** -\> DACH

Answer 30

Covalent binding to PURINE (A, G) bases * Binds RNA\>DNA\>protein Form bi-functional adducts * Binds preferentially to N7 of guanine or adenine * \>90% intrastrand crosslinks (rest interstrand)

Answer 31

60% 30% 10% \<2%

Answer 32

Adducts cause DNA to bend around platinum compounds - local denaturing - ds DNA breaks - cell death * Apoptosis = mediated thru MMR genes (p53, bcl2, bax) * Non-apoptotic mechanisms = overwhelming DNA damage associated w/ non-apoptotic death **Cell cycle non-specific**

Answer 33

**Cisplatin** -\> although cell cycle non-specific, forms cross-links with greatest efficiency during S-phase – * Synergistic w/ agents that reduce intracellular levels of purine and pyrimidine precursors needed for DNA replication/repair; Examples? • ***5-FU and Gemcitabine*** **Oxaliplatin** -\> downregulates thymidylate synthase * ***Synergistic w/ anti-metabolites*** Additive effects with: * Agents that alter mitosis (Paclitaxel) * Inhibitors of DNA repair (PARP or ERCC1)

Answer 34

**Cisplatin** * Prolonged t1/2 (2-3 days) * Rapidly binds plasma proteins (\>90%) * Highly renal toxic * Enhances immune-mediated cell-killing **Carboplatin** * More stable, less toxic * Excretion depends primarily on?? • * GFR and renal clearance * Dosed by? • AUC Oxaliplatin * A divalent oxalate salt * Not entirely cross-resistant with cisplatin/carboplatin * More stable, less toxic * Cyclohexyl substitution may alter susceptibility to repair of DNA adducts - Reduces DNA repair efficiency and increasing cell killing

Answer 35

Diffusion Active transporters (copper pumps – CTR1, ATP7A, ATP7B) Inactivated in the bloodstream/cells by conjugation to sulfhydryl groups 90% eliminated in urine

Answer 36

1. **Altered cellular accumulation** - Inactivation of CTR1 and Increased efflux by ATP7A/B 2. **Cytosolic inactivation of drug** - Via glutathione, metallothionein 3. **Altered DNA repair** - Increased NER -\> \*\*NER responsible for repair of platinumDNA damage (repairs bulky adducts). Increased ERCC1 (NER gene) 4. **Resistance to apoptosis -** Decreased MMR ! can’t link unrepaired DNA damage to apoptotic pathways. Defective MMR proteins (p53, bcl, bax)

Answer 37

Renal * Cation wasting (Mg2+, Ca2+) * Distal tubules more affected than proximal tubules • Cisplatin in most reactive and interacts w/ tubules * Elevated creating may not be good indicator of reduced renal function * Treat with vigorous IV hydration before and after

Answer 38

* Myelosuppression (carbo \>\> cisplatin) – DLT of carbo * GI (cisplatin \>\> carbo) * Fatal pulmonary edema (Cisplatin – cats) * Neurotoxicity and ototoxicity (cisplatin \>\> carbo) Peripheral sensory neuropathy most common – Rarely see cortical blindness, seizures – Ototoxicity d/t loss of hair cells in cochlea * Carcinogenesis – Increased risk of secondary AML * Acute hypersensitivity reaction * SAIDH

Answer 39

Camptothecin – Topotecan – Irinotecan

Answer 40

**ANTHRACYCLINES** * Doxorubicin • Daunorubicin • Idarubicin • Epirubicin **ANTHRACENEDIONES** * Mitoxantrone **EPIPODOPHYLLOTOXINS** * • Etoposide (VP-16) • Teniposide (VP-26)

Answer 41

Nuclear enzymes that relax double-stranded DNA Create transient breaks (“nicks”) to facilitate DNA unwinding for DNA replication and RNA transcription Topo I -\> creates **single-stranded** nicks at 3’ end Topo II -\> creates **double-stranded** nicks at 5’ end

Answer 42

– Bind and stabilize DNA/topo cleavable complex - prevents religation – Irreversible damage results when advancing replication fork encounters complex • Lethal ds breaks = cell death

Answer 43

topo I bound to DNA at ss DNA break site DNA replication • Transcription • DNA repair • Chromosome condensation/separation Most effective in S-phase, but not 100% cell cycle specific

Answer 44

Camptothecan which has high toxicity Non-enzymatic hydrolysis and UGT glucuronidation • Low bioavailability Renal excretion • Reduce dose with renal disease • DLT = myelosuppression • GI (stomatitis, late onset diarrhea) • Increased liver enzymes • Alopecia • Skin rash

Answer 45

Activation by carboxylesterases - becomes SN-38 • Inactivated by glucuronidation in liver **Toxicity is same as topotecan** **DLT = myelosuppression and diarrhea** • Can also see pulmonary toxicity and cholinergic syndrome

Answer 46

Alterations in topo I * Mutations -\> decreased activity or impaired binding by drug Altered drug accumulation in cells * Example = decreased activation of irinotecan by carboxylesterases Alteration of cell response to topo I/drug compound

Answer 47

Antitumor antibiotics derived from Streptomyces bacterium doxorubicin, daunorubicin epirubicin, idarubicin

Answer 48

**Topoisomerase II inhibition** * Binds topo II and prevents religation of DNA ds breaks **DNA intercalation** * Inserts between base pairs perpendicular to long axis of helix ! partial unwinding of helix * Doxorubicin binds w/ high affinity to 5’-TCA * \*\*Most of DNA is in chromatin form ! protects against this type of reaction **Inhibition of DNA helicases** * Helicases -\> dissociate ds DNA into ss DNA * Inhibits strand separation and thus replication

Answer 49

**Quinone ring metabolized to semiquinone radical** * Formed by one electron reduction Main mechanism of cardiotoxicity Note: two electron reduction = pathway of drug inactivation

Answer 50

Cell membrane damage -\> apoptosis via Fas/FasL and activation of sphingomyelin pathway DNA base damage Mitochondrial membrane injury – Release of cytochrome C -\> APOPTOSIS – Decreased energy due to disruption of e- transport chain -\> NECROSIS Altered calcium sequestration

Answer 51

Binds phospholipids via iron chelation Activates sphingomyelin pathway • Formation of ceramide ! activates PKC ! activation of proapoptotic caspases ! apoptosis

Answer 52

Via alterations in cell membrane, DNA damage, free radical formation Induces cellular senescence – Antiangiogenic effects – Targets tumor stem cells NON-SPECIFIC

Answer 53

Enhanced drug efflux by MDR1, MRP1/7, and BRCP Altered topo II activity – Decreased top IIα mRNA and protein via decreased expression or mutations Alteration in ability of cell to undergo apoptosis – Overexpression of bcl-2 or underexpression of p53 Loss of MMR genes/MMR deficiency -\> increased DNA repair ability Increased cellular glutathione -\> reduces free radical formation

Answer 54

**Increase intracellular iron** – Release from ferritin or microsomes – Enahnce transferrin-mediated uptake into cells **Anthracyclines are powerful metal chelators** **OH-quinone binds ferric iron** (anthracycline-iron complex) leading to --\> – Iron-mediated cell membrane damage • Via oxidative destruction – Oxidization critical sulfhydryl groups – Binding of DNA directly • Different than intercalation mechanism **Iron plays role in free radical formation**

Answer 55

1) Enzymatic conversion – Causes reduction of side chain carbonyl to alcohol • Hepatic aldo-ketoreductase family and carbonyl reductase in heart and liver – This step decreases cytotoxicity but increases cardiotoxicity • Doxorubicin is converted to doxorubicinol (cardiotoxic) • Daunorubicin is converted to daunorubicinol (less cardiotoxic) • 2) One-electron reduction -\> free radical formation – To semiquinone free radical by flavin dehydrogenases – Can occur anywhere in the cell 3) Two-electron reduction – Forms unstable quinone methide – Degrades to aglycone species (much less active) or inactive metabolites

Answer 56

Highly protein bound (60-70%) Biliary excretion –\<10% renally excreted (can cause reddish/ orange discoloration of urine) Reduce the dose by 50% with tbili \> 1.5 Proportional to AUC, peak drug levels

Answer 57

Myleosuppression (DLT) Gastrointestinal (DLT) Mutagenic and carcinogenic – Risk of secondary AML in humans Renal failure (cats \>\>\> dogs) Hypersensitivity – why? – Histamine release Radiosensitizer – Can also cause radiation recall

Answer 58

– Ice area – Dexrazoxane – DMSO – Vitamin E – Steroids

Answer 59

Acute -\> arrhythmias and heart blocks Chronic -\> dilated cardiomyopathy – Correlates with peak drug levels (NOT AUC) – Cumulative toxicity 180mg/m2 and even more so when reach \> 240mg/m2 Early on -\> disruption of myofibrils Late -\> vacuolization, myofibrillar loss in the myocardium, and diffuse myocardial fibrosis

Answer 60

Injury of SR ! calcium release and inhibition of calcium sequestration ! decreased ATP levels Inhibition of NADH dehydrogenase ! upsets electron transport chain in mitochondria Lipid membrane peroxidation Oxidation of myoglobin Iron delocalization

Answer 61

Inhibition of mitochondrial cytochrome oxidase Direct oxidation of ryanodine receptor sulfhydryls Down regulation of β-adrenergic receptors Inhibition of specific cardiac mRNAs for α-actin and troponin-I Directly toxic to cardiac progenitor cells

Answer 62

Low levels of cardiac catalase Leaves glutathione peroxidase as only pathway for hydrogen peroxide detoxification

Answer 63

**Iron chelator** that can prevent cardiotoxicity **Topo II inhibitor** (be aware that this is chemo) Is a **prodrug** that undergoes activation by hydrolysis at physiologic pH * Markedly enhanced by rapid conversion to active drug in cardiac myocytes

Answer 64

Daunorubicin -\> original anthracycline isolated from Streptomyces Doxorubicin -\> modified structure of daunorubicin – More active, more cardiotoxic Idarubicin -\> orally absorbed daunorubicin analog – DLT in dogs – myelosuppression Epirubicin -\> differs from doxorubicin in 3D conformation – No convincing evidence that Ida and Epi are less cardiotoxic than doxorubicin (but some studies show this) – DLT in dogs - GI

Answer 65

Pegylated liposome-encapsulated doxorubicin Extends t_1/2 (by 40x), Limits distribution, Less BM toxicity and cardiotoxicity

Answer 66

Palmar plantar dysthesia -\> progressive accumulation of tender nodules, erythematous desquamation on palms and soles of feet Must d/c drug if see this Vitamin B6 (pyridoxine) lowers risk 4x

Answer 67

DNA intercalation-\> inhibition of DNA/RNA synthesis • Preference for GC base pairs – Much less free radical formation (differs from anthracyclines) Hepatic metabolism. Reduce dose by 50% w/ elevated tbili MDR (increased Pgp, MRP, BCRP). Decreased expression of topo II. Modification of apoptotic program – **Myelosuppresion (DLT)** – GI – Turns fingernails, sclera, urine blue – Less cardiotoxic but can still oxidize critical sulfhydryl groups on ryanodine receptors in the SR – Radiosensitizer – **NOTE: can be given intracavitary**

Answer 68

Semisynthetic glycoside derivatives of podophyllotoxins – Antimitotic agent derived form the mandrake plant Pure topo II inhibitor -\> apoptosis Biliary (minor), renal (major). Reduce dose with hepatic and renal disease. PO. Synergism between platinum agents and etoposide Myelosuppression (DLT) – Carcinogenic – GI – Hypersensitivity – Radiosensitizer

Answer 69

Methotrxate - folic acid analog (antifolate) Direct thymidylate synthase inhibitors * Raltitrexed * Premetrexed

Answer 70

Pyrimidine and purine analogs Pyrimidines (C, U, T) * 5-FU - inhibit thymidylate synthase * Capecitabine - inhibit thymidylate synthase * Cytosar - cytidine analog * Gemcitabine - cytosine analog

Answer 71

Purine (A,G) * 6-mercaptopurine (6-MP) - guanine analog * 6-mercaptopurine (6-MP) - guanine analog * Azathioprine - guanine analog * Fludarabine ! adenosine analog

Answer 72

Drugs that interfere with normal cellular functions, particularly DNA synthesis S-phase specific BM and GI Duration above a critical threshold and NOT peak drug levels Do not directly interact with DNA – Do not cause carcinogenesis

Answer 73

**Competitive inhibitor of dihydrofolate reductase (DHFR)** ## Footnote - Prevents formation of reduced folates (active form) - Reduced folates are important in DNA synthesis by: Transferring of methyl group to form PURINES and Converting dUMP to dTMP (catalyzed by THYMIDYLATE SYNTHASE) – Reduced folate is oxidized in this reaction – Need DHFR for reduction to its active form – Increased dUMPs -\> incorporation of U instead of T into DNA -\> DNA breaks

Answer 74

Depletion of dTMPs (thymidine monophosphate) and purines by polyglutamated forms of methotrexate – Leads to decreased DNA synthesis -\> DNA strand breaks -\> apoptosis

Answer 75

Converts dihydrofolic acid (FH2) to tetrahydrofolic acid (FH4) using NADPH as an electron donor * FH4 is the reduced form of folic acid * Folic acid compounds are active as coenzymes only in a reduced form

Answer 76

Methotrexate is metabolized by polyglutamation Retains MTX/folates intracellularly -\> increases effectiveness of DHFR inhibition – NOTE: optimal binding of MTX to DHFR (and cytotoxicty) depends on NADPH and polyglutamate forms

Answer 77

– Reduced folate carrier system (RFC) -\> primary transport mechanism for MTX and reduced folates (including Leucovorin) – Folate receptor system – pH sensitive transport system -\> mediates folate transport into CNS

Answer 78

folylpolyglutamyl synthetase (FPGS)

Answer 79

Optimal binding depends on NADPH and PG-MTX

Answer 80

• Mutations in RFC or DHFR – MTX can’t bind to either * Increased MRP-1(2,3) and BCRP * Defects in polyglutamation * Increased DHFR concentrations

Answer 81

**Metabolism** – Polyglutamation in tissues – 7-hydroxylation in liver **Elimination** – Intact in urine • Reduce dose with renal disease – Biliary excretion plays small role • Can give PO – Crosses BBB but only at very high doses (used for CNS lymphomas/leukemias in humans)

Answer 82

* Myelosuppresion (DLT) * GI/mucositis (DLT) * Renal (w/ high doses) * Hepatotoxicity (fibrosis w/ long term use) * Neurotoxicty * Pneumonitis (self-limiting) * Hypersensitivity

Answer 83

Methotrexate – Drug interactions ## Footnote • L-asparaginase (blocks MTX toxicity) – why? – Decreases protein synthesis and prevention of cell entry into S-phase – When Lspar given w/ MTX to dogs, no alleviation of GI signs d/t MTX (Bortnowski et al, AJVR 1991) • NSAIDs -\> aspirin (enhances MTX toxicity) – Decreases renal clearance • 5-FU and cytosar – When MTX is given before, inhibits purine synthesis and increases nucleotide formation -\> increases activation of these drugs

Answer 84

Drug concentration and duration of cell exposure – Duration of cell exposure much more important Presence of purine bases/nucleosides and thymidine Increased concentration of reduced folates

Answer 85

Leucovorin Derivative of tetrahydrofolic acid that does not require DHFR for conversion Allows for some purine/pyrimidine synthesis to occur in presence of DHFR inhibition

Answer 86

Converts dUMP to dTMP (thymidine monophosphate) Requires cofactor 5,10-methylene-tetrahydrofolate dTMP -\> is phosphorylated to thymidine triphosphate for DNA repair and synthesi

Answer 87

Bind 5,10-methylenetetrahydrofolate – A cofactor that aids in conversion of dUMP to dTMP (ie thymidine) – Forms complex with TS causing inhibition Raltitrexed - Inhibits TS, DHFR, and GARTF Premetrexed - Inhibits TS, GARTF Renally excreted Toxicity – Myelosuppression, Pulmonary infiltrates, Rash • Toxicity lessened by: – Folic acid, Vitamin B12

Answer 88

– \*\*Inhibits THYMIDYLATE SYNTHASE (TS) ! causes depletion of dTMPs ! decreased DNA synthesis – Is incorporated into DNA ! triggers DNA repair and strand breaks ! APOPTOSIS – Is incorporated into RNA leading to rRNA/mRNA inhibition

Answer 89

Inhibition of TS = inhibition of DNA synthesis • Cell cycle specific (s-phase) – Inhibition of RNA processing, function, and translation • Cell cycle non-specific

Answer 90

– 5-FUTP - incorporated into RNA – 5-dUTP - incorporated into DNA – 5-FdUMP - inhibits TS

Answer 91

* Decreased activity of activating enzymes * Increased nucleotide pool size * Overexpression of mutation of TS - decreased binding

Answer 92

**Converted to active drug intracellularly by multiple pathways** **90% eliminated by metabolism/catabolism** • Mediated by DPD (dihydropyrimidine dehydrogenase) – NOTE: people with DPD polymorphism (leading to deficiency) will have significantly increased toxicity!! • Liver is major site (although can occur in a variety of other tissue types) – \<10% excreted in urine unchanged

Answer 93

Can be given orally, as IV bolus, as a CRI, and can be used topically – Bioavailability by oral route is highly variable – Reported toxicities in dogs/cats after oral ingestion (of pills or tubes of cream) and IV **– Crosses BBB!**

Answer 94

\*\*Non-linear pharmacokinetics – Due to saturation of metabolism at higher doses – Toxicity depends on schedule * IV -\> t1/2 = 8-14 mintues; eliminated rapidly from plasma; causes more severe myelosuppression compared to CRI * CRI -\> steady state achieved after 12-24 hrs; GI (muscositis in pple) is DLT when given as CRI – Total body clearance decreases with increasing dose • Clearance is faster with CRI schedules

Answer 95

* Myelosuppression (IV \>\> CRI) * GI/Mucositis (DLT w/ CRI) * Dermatologic (IV and CRI) – Alopecia, rash, nail changes – Plamar-plantar erythrodysesthesia (CRI) • Neurotoxicity – Acute and delayed -\> seizures (acute), demyelination (delayed) • Cardiotoxicity – Depletes high energy phosphate compounds in the myocardium ! Do not use in cats! coronary vasospasm • Ocular – Irritation, conjunctivitis, keratitis • Pulmonary edema/congestion

Answer 96

**– Leucovorin** * Must be given before 5-FU * Increases the pool of folate cofactor (5,10-MTHF) that compete with F-FdUMP and TS ! this decreases dissociation rate ! potentiates TS inhibition **– DPD inhibitors** • Decreases 5-FU metabolism **– Methotrexate** * Must be given BEFORE 5-FU * Inhibits purine biosynthesis and elevates cellular pools of PRPP (phosphoribosyl phosphate) ! increase activation of 5-FU **– Platinum analogs** * 5-FU decreases dTTP pools ! inhibits DNA repair * Oxaliplatin down-regulates TS expression **– Irradiation** • 5-FU decreases dTTP pools ! inhibits DNA repair

Answer 97

– Allopurinol • Inhibits OPRT (normally activates 5-FU)

Answer 98

* Oral prodrug converted to 5-FU in the tumor * Metabolized in liver to 5’DFCR * 5’DFCR converted to 5’DFUR by cytidine deaminase in the liver and in tumor tissue * 5’DFUR converted to 5-FU by thymidine phosphorylase (TP) * NOTE: TP concentration is higher in tumors than in normal tissues

Answer 99

Cytidine analog **– \*\*Incorporated into DNA -\> loss of template function and chain elongation** * Stalls replication fork for cells in active DNA synthesis * Activates ATR and Chk1 (checkpoints that allow DNA repair) Absence of either checkpoint sensitizes cells to apoptosis Levels of apoptotic proteins influence response **– Competitive inhibitor of DNA polymerase (α \>β)**

Answer 100

Carrier mediated process via hENT1 Cytosar = AraC - Must be converted to active form by 3 enzymes: * CdR kinase ! \*\*Rate limiting step (Ara-CMP) * dCMP kinase (Ara-CDP) * NDP kinase (Ara-CTP)

Answer 101

– Deamination – In liver, tissues, and plasma

Answer 102

Rapid disappearance from plasma d/t deamination – Elimination t_1/2 is roughly 60min in the dog – Best to be given as CRI to increase duration of exposure since this is a cell-cycle specific drug **Crosses BBB** **Route of administration** – Generally given as CRI – SC * Equivalent drug exposure (AUC) same as w/ CRI * Steady state in plasma not achieved in dogs when given SC compared to CRI Crook et al (Vet Pharm Therap, 2012) – SC administration may not be as effective at leading to penetration of BBB compared to CRI – IP – Intrathecally – Not routinely given PO d/t high concentrations of cytidine deaminase in the GI mucosa and liver

Answer 103

* Decreased kinases (most common to see decrease in cytidine kinase) * Increased deaminases * Decreased nucleoside transport into the cell * Increased dCTP pools (competes w/ ara-CTP) * Increased expression of antiapoptotic proteins – Bcl-2 and Bcl-XL

Answer 104

* Myelosuppression (all 3 cell lines) – DLT * GI/mucositis – DLT * Intrahepatic cholestasis * Pancreatitis * High doses: – Non-cardiogenic pulmonary edema – CNS toxicity – Eccrine hydradenitis (febrile cutaneous reaction with plaques/nodules) – Conjunctivitis

Answer 105

– Alkylating agents and cisplatin -\> cytosar inhibits repair of DNA-alkylator adducts – Hydroxyurea -\> decreases dCTP pools and increase ara-CTP formation – Methotrexate -\> increases ara-CTP formation – Topo II inhibitors-\> cytosar increases levels of topo II

Answer 106

Cytosine analog ## Footnote – **Incorporated into DNA** -\> loss of template function and chain elongation -\> inhibits DNA synthesis – **Inhibits ribonucleotide reductase** * Leads to decreased biosynthesis of deoxyribonucleoside triphosphate precursors -\> decreased DNA synthesis * Inhibits DNA polymerase -\> inhibits DNA repair

Answer 107

hENT transported (same as cytosar) ## Footnote Phosphorylated by CdR kinase to dFdCTP and dFdCDP: • dFdCTP – Competes w/ dCTP as weak inhibitor of DNA polymerase – Substrate for incorporation into DNA ! DNA strand termination • dFdCDP – Inhibits ribonucleotide reductase – Subsequent decrease in dATP, dCTP, dGTP, and dTTP pools

Answer 108

– Deamination in liver, plasms, and tissues – Reduce dose with elevated serum bilirubin

Answer 109

* Decreased CdR kinase * Increased deaminase * Increased ribonucleotide reductase * Decreased nucleoside transport

Answer 110

• Myelosuppression – DLT – Longer duration infusions lead to greater myelosuppression * GI – epithelial ulceration * Flu-like symptoms * Thrombotic microangiopathy -\> hemolytic uremic syndrome * Pulmonary toxicity

Answer 111

– Inhibits NER -\> responsible for repair of platinum-DNA damage (repairs bulky adducts) – Incorporation into DNA induces structural changes in DNA helix -\> increased adduct formation by platinums

Answer 112

– Guanine analogs – Analog of hypoxanthine – Activated intracellularly by HGPRT – Extensive hepatic and cellular metabolism – Eliminated by xanthine oxidase and TPMT – Azathioprine: prodrug of 6-MP -\> 90% non-enzymatically converted to 6-MP by sulfydryl-containing compounds

Answer 113

– \*\*Incorporation of metabolites into DNA and RNA -\> leads to APOPTOSIS thru MMR – Inhibits de novo purine synthesis – S-phase specific

Answer 114

– Allopurinol -\> decreases elimination – Mesalamine, sulphasalazine, and osalazine inhibit TPMT **Toxicity** – Myelosuppression – Mild GI – Hepatoxicity – Immunosuppression • G-TGTP (a metabolite) binds Rac1, which plays a role in T-cell development -\> leads to apoptosis of T-cells

Answer 115

Cats - have lower levels of TPMT Certain humans w/ genetic deficiency of TPMT will have increased toxicity (screening tests available)

Answer 116

– Incorporation of fraudulent nucleotides into DNA and RNA * 6-TG not converted to 6-methyl thioinosine triphosphate ! effects on purine metabolism are less than 6-MP (and azathioprine) * All other characteristics similar to 6-MP

Answer 117

• General characteristics – Adenosine analog – Activated intracellularly by dCd kinase to F-ara-ATP – Renally excreted

Answer 118

• MOA – Incorporation into DNA as false nucleotide ! apoptosis – Inhibition of DNA polymerase, primase, ligase – DNA chain termination – Inhibition of ribonucleotide reductase • Drug interactions – Increases cytotoxicity of cytosar and platinums • Toxicity – Myelosuppression – Immunosuppression – Neurotoxicity (at high doses) – Interstitial pneumonitis (rare) – Hemolytic anemia (rare)

Answer 119

Elevation of ribonucleotide reductase activity

Answer 120

Great oral bioavailability (80-100%) Metabolism not completely known – Possibly liver – Many enzyme systems are capable of metabolism Renally excreted -\> reduce dose w/ renal dz

Answer 121

* Myelosuppression (DLT) * GI (mild) * Dermatologic changes -\> hyperpigmentation, erythema, skin ulcerations * Nailbed changes -\> atrophy, pigmented nail beds * Carcinogenic/teratogenic * Rarer effects: – Transient increase in BUN/creat, proteinuria – Hepatotoxicity – Interstitial pulmonary disease – Fever

Answer 122

**– Purified from Escherichia coli (formulation we use)** **– Purified from Erwinia carotovora (chrysanthemi)** **– PEGylated L-asparaginase** * Reduced antigenicity * Longer t_1/2 * Used in humans when they develop hypersensitivity to E. coli or E. carotovora formulations

Answer 123

Enzyme non-essential amino acid Synthesized by transamination of L-aspartic acid * Amino group donated by glutamine * Reaction catalyzed by L-asparagine synthetase

Answer 124

Malignant lymphocytes lack asparagine synthetase (AS) – Cannot synthesize asparagine -\> decreased protein synthesis -\> APOPTOSIS – Asparagine = non-essential amino acid; normal cells contain AS and can synthesize asparagine * Hydrolysis of L-asparagine in tumor cells-\> NH3 (ammonia) + aspartic acid * Maximal effect in G₁

Answer 125

**• Up-regulation of asparagine synthetase in tumor cells** – Associated with hypomethylation of AS gene **• Neutralizing antibodies** – Kidd et al (VCO 2013) 30% of dogs developed antibodies after single injection 47% of dogs developed antibodies after multiple injections **Defective induction of apoptosis**

Answer 126

– Metabolic degradation – Immune clearance – Does not cross BBB but depletes asparagine in the CSF

Answer 127

– Decreased toxicity of methotrexate -\> d/t inhibition of protein synthesis and prevention of entry into S-phase of cell cycle • When Lspar given w/ MTX to dogs, no alleviation of GI signs d/t MTX (Bortnowski et al, AJVR 1991) – Increased toxicity when given w/ vincristine d/t decreased hepatic clearance and thus prolonged t1/2

Answer 128

– Decreased protein synthesis – Immunologic sensitization

Answer 129

– Decreased albumin – Decreased insulin -\> hyperglycemia – Increased serum lipoproteins and triglycerides – Coagulation abnormalities -\> decreased clotting factors and antithrombin • Can see thromboembolism, less commonly bleeding

Answer 130

**– Nausea, vomiting, fever chills** – Hypersensitivity reaction (decreased w/ PEGylated version) – CNS dysfunction -\> coma, seizures, confusion * Thromboembolic events * Increased ammonia (case report in a dog) – Pancreatitis • May be d/t hypertriglyceridemia – Liver function test abnormalities • May be d/t mobilization of lipids – May suppress immune function and contribute to higher rates of infection in Lspar treated patients

Chemotherapy Flashcards

(162 cards)