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Chemotherapy > Chemotherapy > Flashcards

Chemotherapy Flashcards

1
Q

What is half-life?

A

Time required for plasma concentration to decrease by ½

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2
Q

When the amount of drug coming equals the amount of drug going out?

A

Steady state

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3
Q

What is C0 (or Css)?

A

Initial steady state concentration of drug in plasma

– Drugs with short half-lives reach steady state quickly, while those with long half-lives take longer to reach steady state

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4
Q

What is Cmax?

A

peak plasma concentration

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5
Q

What is bioavailability?

A

Amt of drug available after PO administration/amt available after IV admininstration

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6
Q

What is CL?

A

Drug clearance (= dose given IV/AUC)

Volume of plasma from which the drug is completely removed per unit of time

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7
Q

What is Vd?

Related to what?

A large volume of distribution represents what?

A

Volume of distribution

Relates total amount of drug in the body to plasma concentration

Extensive tissue binding

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8
Q

What is linear PK?

A

Plasma concentration of a drug declines in an exponential manner following IV dosing

Plasma concentration is directly proportional to dose

AUC increases proportionately to dose

Other parameters (ie CL and Vd) are independent of dose

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9
Q

What is non-linear PK?

A

Exponential characteristics at low doses and downward curvature at high doses

Clearance decreases as dose increases

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10
Q

What does bolus injection accomplish?

For what kind of drugs?

A

Provides maximum peak level

Good for cell-cycle non-specific drug

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11
Q

What does CRI accomplish?

Good for what kind of drugs?

A

Provides duration of exposure above a threshold concentration

Good for cell-cycle specific drugs

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12
Q

What are the 3 classes of anti-mitotic (antimicrotubule) drugs?

A

Vinca alkaloids: Vincristine sulfate (Oncovin) – Vinblastine sulfate (Velban) – Vinorelbine tartrate (Navelbine) – Vindesine sulfate (Eldisine) – Vinflunine ditartrate (Javlor)

Taxanes: Paclitaxel (Taxol) – Docetaxel (Taxotere) – PBPPI – protein bound paclitaxel particles for injection (Abraxane)

Epothilones: Ixabepilone

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13
Q

Vinca alkaloids are derived from what?

A

Pink periwinkle plant (Catharanthus roseus)

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14
Q

General structure of vinca alkaloids?

A

Dihydroindole nucleus (vindoline) = major alkaloid in the periwinkle plant

Linked to indole nucleus (catharanthine) = found in smaller quantities in periwinkle plant

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15
Q

Differences between vinca alkaloids

VCR and VBL? what groups?

VRL? Unique property?

Tubulin-binding affinities

A

Naturally occurring. Vcr possesses formyl group / Vbl possesses methyl group

Semisynthetic derivative of vbl - Modified catharanthine nucleus. 300x concentration in lung compared to plasma levels

vcr>vbl>vrl (vcr is more neurotoxic)

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16
Q

What is the microtubule structure?

A

Composed of tubulin: heterodimer = α and β tubulin

Assemble into linear protofilaments (PFs)

Each MT composed of 13 PFs

Arrange into a helix with one turn = 13 tubulin dimers

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17
Q

Microtubule structure has 2 ends (treadmilling)

Minus versus plus?

A

Minus - α-tubulin exposed, assembly slow = net shortening

Plus - β-tubulin exposed, assembly fast = net elongation

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18
Q

Microtubule function

Principle component of what? What does it do?

Other improtant functions?

Other roles?

A

Mitotic spindle (MS) - Separates chromosomes into two daughter cells during cell division

Integrity of MS needed to pass thru cell-cycle check points • Errors in chromosome segregation –> APOPTOSIS

Plays role in interphase functions – Maintaining cell shape – Scaffold for cell organelles – Motor proteins –> help cellular constituents move

Secretion; Neurotransmission; Relaying signals between cell surface receptors and nucleus

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19
Q

MOA of vinca alkaloids

A

Bind rapidly and reversibly to TUBULIN –> inhibition of microtubule assembly – Block at metaphase/anaphase boundary in mitosis –

Mitotic spindle blocked - decreased tension at kinetechores - chromosomes stuck at spindle poles - signal to anaphase-promoting complex blocked –> APOPTOSIS

Most damage occurs during S-phase but cells die in Mphase; can perturb cells in non-mitotic phases of cell cycle = cell-cycle non-specific

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20
Q

How does different concentrations of vinca alkaloid work?

A

Lower concentrations –> inhibits assembly of MTs

Higher concentrations –> binds along sides of MTs leading to disintegration

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21
Q

What are some other effects of vinca alkaloids?

A

Decreased intracellular transport of amino acids

Inhibit DNA/RNA/protein synthesis

Disrupt cell membrane integrity

Inhibit glycolysis

Alter intracellular movement of organelles

Maintains structural integrity of platelets • Used for ITP (vcr)

Decreases angiogenesis –> Blocks endothelial cell proliferation, chemotaxis, and spreading of fibronectin

Radiosensitizer –> Due to the ability to block cell cycle in G2/M phase

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22
Q

4 MOR for vinca alkaloids?

A

MDR (Pgp/MDR1 and MRP1)

Alterations in α and β subunits of tubulin

Increased expression of microtubule associated proteins (MAPs)

Alterations in apoptotic pathway

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23
Q

PK of vinca alkaloids (list 4)

Metabolized by what?

A

Large volume of distribution

Doesn’t cross BBB

Significant platelet binding due d/t large tubular component in platelets

Long terminal half-life –> Vcr longest t1/2 ! increased risk of neurotoxicity

Extensive hepatic metabolism and biliary/fecal excretion (70-80%) – Metabolized by cytochrome P450

Dose reductions with elevated tbili (humans) •50% dose reduction if tbili = 1.5-3.0 mg/dL • 75% dose reduction (at least) if tbili > 3.0 mg/dL – 10-20% renal excretion (no dose reduction needed for renal insufficiency

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24
Q

Toxicity of Vinca Alkaloids

What is DLT for vbl/vrl?

What is DLT for vcr?

4 other toxicities?

A

Myelosuppression

Neurotoxicity (DLT for vcr) – Mixed sensory-motor and autonomic polyneuropathy – Related to total cumulative dose

GI –> ileus, constipation. Most common w/ vbl in people and vcr in cats

Hyper/hypotension (autonomic neurotoxicity)

SIADH

Pulmonary –> hypersensitivity or pulmonary infiltrates

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25
Q

Vinca alkaloid is a ____?

What do you do if they extravasate?

A

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

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26
Q

3 drug interactions for vinca alkaloid?

A

ELSPAR –> Reduces hepatic clearance of vcr

Methotrexate –> Vinca alkaloids block efflux leading to increased intracellular accumulation

Cytochrome P450 inhibitors –> Increases toxicity of vinca alkaloids

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27
Q

Taxanes are derived from what?

What are the 2 drugs and if naturally occuring or synthethic and vehicle?

A

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)

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28
Q

Main MOA of Taxanes?

How do they work at high and low concentrations?

How does this differ form vinca alkaloids?

A

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

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29
Q

Taxanes lead to mitotic block at ?

MT disruption induces?

Specific for what phase?

A

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

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30
Q

List 6 other effects of taxanes?

A

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

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31
Q

3 MOR of taxanes

A

MDR (MDR1 and MDR2)

Alteration in tubulin binding sites

Decreased apoptosis d/t altered cell signaling

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32
Q

PK of taxanes

Metabolism?

4 other characteristics?

A

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

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33
Q

What is the oral bioavailability of taxanes poor?

How can you increase oral absorption?

A

– 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

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34
Q

Waite et al (Phase II study) –

Oral docetaxel/cyclosporine A in dogs w/ epithelial tumors (VCO 2012)

51 dogs

17% response rate – 50% (6/12 dogs) with oral SCC exhibited a response Main toxicity was GI

A
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35
Q

DLT of taxanes?

2 other toxicities

A

neutropenia (3-5 day nadir)

Type I hypersensitivity (to carrier molecule), GI rare

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36
Q

Toxicities with Paclitaxel

A

–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
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37
Q

Toxicities with Docetaxel

A

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)

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38
Q

List 5 nitrogen mustards?

List 4 nitrosureas?

Other?

Methylating agents?

A

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)

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39
Q

MOA of alkylating agents?

Where do the drugs atttack?

Nitrogen mustards?

Nitrosureas?

Methylating agent?

A

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

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40
Q

How do alkylating agents enter cells?

What 2 drug are different?

List 2 MOAs?

Cell cycle specic or non-specific?

A

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

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41
Q

What is a bifunctional alkylating agent? Examples?

A

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
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42
Q

How is damage caused by mono-functional alkylating agents repaired?

A

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
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43
Q

Other mechanisms of repair for alkylating agents?

A

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

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44
Q

Cyclophosphosphamide

Bi- or mono functional? targets?

Metabolism?

Ifosfamide?

A

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

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45
Q

PK of oral and IV cyclophosphamide in dogs with LSA (Warry et al JVIM 2011)

A

Drug exposure to cyclophosphamide after IV significantly higher than PO

– First past elimination through the liver

No significant difference in exposure to 4- OHCP

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46
Q

What is unique about cyclophosphamide?

A

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
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47
Q

Cyclophosphamide/Ifosfamide - PK

List 3

A

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

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48
Q

Cyclophosphamide/Ifosfamide - Toxicity

What is the DLT?

List 7 other toxicities?

A

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

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49
Q

Mutargen is derived from?

Metabolism?

A

Mustard gas

Metabolized in plasma, excreted in urine

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50
Q

Alkylating agents - MOR

A
  • 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
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51
Q

Alkylating agents - Mechanisms of decreasing resistance

A
  • 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)
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52
Q

4 Platinum agens?

A

Cisplatin • Carboplatin • Oxaliplatin • Satraplatin

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53
Q

What is the structure of Platinum agents?

A

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)
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54
Q

PK differences of platinum agents is due to?

Cisplatin?

Carboplatin?

Oxaliplatin?

A

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

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55
Q

What is Platinum Agents - MOA

A

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)
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56
Q

Pltainum agents MOA

GpG adduct?

ApG addufct?

GpXpG adduct?

Interstand?

A

60%

30%

10%

<2%

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57
Q

What do the adducts do when formed by Platinum agents?

Cell cycle specific or non-specific?

A

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

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58
Q

Platinum Agents- Synergistic/Additive effects

Cisplatin is synergistic with?

Oxaliplatin synergistic with?

List 2 additive effects?

A

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)
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59
Q

Platinum Agents – Differences

List 4 characteristics for cisplatin

How is carbo dosed?

A

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
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60
Q

Selting et al (JVIM 2011)

eval of Satraplatin (JM216) in dogs w/ malignant tumors

MTD 30-35mg/m2/d x 5d q28d

DLT = myelosuppression • Typically neutropenia • Plt nadir before neut nadir (14 vs. 19 days)

No neuro or nephrotoxicity noted, mild GI

Bioavailability = 41% • Higher AUC after 5th vs. 1st dose ! what does this suggest? – Drug accumulation in tissues

Dogs w/ OSA treated in adjuvant setting had MST of 577days

A
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61
Q

How do Platinum drug enter/exit cells?

Metabolism?

Elimination?

A

Diffusion

Active transporters (copper pumps – CTR1, ATP7A, ATP7B)

Inactivated in the bloodstream/cells by conjugation to sulfhydryl groups

90% eliminated in urine

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62
Q

4 MOR for Platinum agents?

A
  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)
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63
Q

Platinum Agents - Toxicity

Cisplatin?

A

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
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64
Q

List 7 other toxicities associated with Platinum agents?

DLT for carbo?

A
  • 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
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65
Q

List 3 Topoisomerase I inhibitors?

A

Camptothecin – Topotecan – Irinotecan

66
Q

What are the 3 categories of Topoisomerase II inhibitors and list the individual drugs?

A

ANTHRACYCLINES

  • Doxorubicin • Daunorubicin • Idarubicin • Epirubicin

ANTHRACENEDIONES

  • Mitoxantrone

EPIPODOPHYLLOTOXINS

  • • Etoposide (VP-16) • Teniposide (VP-26)
67
Q

What is topoisomerase?

What is the difference between topo I and II?

A

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

68
Q

General MOA for Topisomerase Inhibitors?

A

– Bind and stabilize DNA/topo cleavable complex - prevents religation

– Irreversible damage results when advancing replication fork encounters complex

• Lethal ds breaks = cell death

69
Q

Topoisomerase I inhibitors - MOA

What is the “Cleavable complex”?

Interferes with what 4 processes?

Most effective in what phase?

A

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

70
Q

Topotecan is similar to what drug?

Metabolism?

Excretion?

List 5 toxocities and what is DLT?

A

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

71
Q

Metabolism of Irinotecan?

Toxicity? DLT?

A

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

72
Q

List the 3 MOR for Topoisomerase I inhibitors

A

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

73
Q

What are Anthracyclines?

Naturally occuring?

Doxorubicin analogues?

A

Antitumor antibiotics derived from Streptomyces bacterium

doxorubicin, daunorubicin

epirubicin, idarubicin

74
Q

List 3 MOA for Anthracyclines?

A

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
75
Q

How do anthracycline create free radicals?

A

Quinone ring metabolized to semiquinone radical

  • Formed by one electron reduction

Main mechanism of cardiotoxicity

Note: two electron reduction = pathway of drug inactivation

76
Q

The generation of free radicals by anthracyclines leads to what 4 effects?

A

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

77
Q

Anthracycline damages cell mmembranes by what 2 ways?

A

Binds phospholipids via iron chelation

Activates sphingomyelin pathway • Formation of ceramide ! activates PKC ! activation of proapoptotic caspases ! apoptosis

78
Q

Anthracyclines also stimulate apoptosis how?

Other MOA?

Cell cycle specific or non-specific?

A

Via alterations in cell membrane, DNA damage, free radical formation

Induces cellular senescence – Antiangiogenic effects – Targets tumor stem cells

NON-SPECIFIC

79
Q

List 5 MOR for Anthracyclines?

A

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

80
Q

Anthracyclines and Iron

A

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

81
Q

Anthracyclines - Metabolism

A

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

82
Q

Anthracyclines – PK parameters

Protein bound?

Excretion?

Antitumor effects are proportional to? Cardiotoxicity?

A

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

83
Q

List 6 toxicities associated with Anthracyclines?

A

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

84
Q

Treatment for extravasation for Anthracyclines?

A

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

85
Q

Anthracyclines – Cardiotoxicity

Acute?

Chronic?

Increased risk at what dose?

Lesions on histopathology early and late phase?

A

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

86
Q

Anthracyclines – Mechanisms of Cardiotoxicity

List 5 oxidative mechanisms?

A

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

87
Q

Anthracyclines – Mechanisms of Cardiotoxicity

List 5 nonoxidative mechanisms?

A

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

88
Q

Why is the heart particularly sensitive to anthracyclines?

A

Low levels of cardiac catalase

Leaves glutathione peroxidase as only pathway for hydrogen peroxide detoxification

89
Q

DEXRAZOXANE (Zinecard) – What is this drug and how does it work?

A

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
90
Q

Specific Anthracyclines

Daunorubicin?

Doxorubicin?

Idarbucin?

Epirubicin? DLT?

A

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

91
Q

What is Doxil?

What does pegylation do?

A

Pegylated liposome-encapsulated doxorubicin

Extends t1/2 (by 40x), Limits distribution, Less BM toxicity and cardiotoxicity

92
Q

What is a specific toxicity of Doxil and how is this treated?

A

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

93
Q

Anthracenediones - Mitoxantrone

MOA?

Elimination?

MOR?

List 5 toxicities? DLT?

A

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

94
Q

Epipodophyllotoxins

Derived from?

MOA?

Excretion?

Etoposide can be adminitered how?

List 5 toxicities? DLT?

A

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

95
Q

List the 3 antifotales?

A

Methotrxate - folic acid analog (antifolate)

Direct thymidylate synthase inhibitors

  • Raltitrexed
  • Premetrexed
96
Q

Nucleoside Analogs include?

List the pyrimidine analogs?

A

Pyrimidine and purine analogs

Pyrimidines (C, U, T)

  • 5-FU - inhibit thymidylate synthase
  • Capecitabine - inhibit thymidylate synthase
  • Cytosar - cytidine analog
  • Gemcitabine - cytosine analog
97
Q

List the 4 purine analogs?

A

Purine (A,G)

  • 6-mercaptopurine (6-MP) - guanine analog
  • 6-mercaptopurine (6-MP) - guanine analog
  • Azathioprine - guanine analog
  • Fludarabine ! adenosine analog
98
Q

How to antimetabolites function?

Cell-cyle specific or non-specific?

Toxicity?

Efficacy depends on?

A

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

99
Q

What is the MOA for Methotrexate?

A

Competitive inhibitor of dihydrofolate reductase (DHFR)

  • 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

100
Q

Another mechanism of action for Methotrexate?

A

Depletion of dTMPs (thymidine monophosphate) and

purines by polyglutamated forms of methotrexate

– Leads to decreased DNA synthesis -> DNA strand breaks ->

apoptosis

101
Q

How does DHFR work?

A

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
102
Q

How does methotrexate metabolism enhance DHFR inhibition?

A

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

103
Q

What are the 3 mechanisms of uptake of Methotrexate into cells (3 mechanisms)?

A

– 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

104
Q

Polyglutamation of MTX is mediated by?

A

folylpolyglutamyl synthetase (FPGS)

105
Q

Inhibition of DHFR?

Depletion of dTMPs and purines -> decreased DNA synthesis -> DNA strand breaks and S->G2 arrest -> APOPTOSIS

A

Optimal binding depends on NADPH and PG-MTX

106
Q
A
107
Q

List 4 MOR for Methotrexate?

A

• Mutations in RFC or DHFR

– MTX can’t bind to either

  • Increased MRP-1(2,3) and BCRP
  • Defects in polyglutamation
  • Increased DHFR concentrations
108
Q

How is Methotrextae metabolized?

Elimination?

• Does this drug cross BBB?

A

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)

109
Q

What are the toxicities associated with methotrexate?

DLT?

A
  • Myelosuppresion (DLT)
  • GI/mucositis (DLT)
  • Renal (w/ high doses)
  • Hepatotoxicity (fibrosis w/ long term use)
  • Neurotoxicty
  • Pneumonitis (self-limiting)
  • Hypersensitivity
110
Q

What are the 3 drug interactions with methotrexate?

A

Methotrexate – Drug interactions

• 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

111
Q

PK factors for methotrexate? Which one is more important?

What 2 factors reduce cytotoxicity?

A

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

112
Q

What is a drug that rescues patients from MTX-induced cytotoxicity?

Drugs MOA?

A

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

113
Q

What is thymidylate synthase?

Needs what to function?

A

Converts dUMP to dTMP (thymidine monophosphate)

Requires cofactor 5,10-methylene-tetrahydrofolate

dTMP -> is phosphorylated to thymidine triphosphate for DNA repair and synthesi

114
Q

The MOA for Thymidylate Synthase Inhibitors?

2 drugs in this category and what do they inhibit?

Excretion?

List 3 toxicities and how can they be lessened?

A

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

115
Q

3 main MOAs for 5-FU?

A

– **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

116
Q

What are the different effects of of 5-FU with regards to cell cycle?

A

Inhibition of TS = inhibition of DNA synthesis

• Cell cycle specific (s-phase)

– Inhibition of RNA processing, function, and translation

• Cell cycle non-specific

117
Q

5-FU is phosphorylated after entering cells and becomes:

A

– 5-FUTP - incorporated into RNA

– 5-dUTP - incorporated into DNA

– 5-FdUMP - inhibits TS

118
Q

3 MORs for 5-FU?

A
  • Decreased activity of activating enzymes
  • Increased nucleotide pool size
  • Overexpression of mutation of TS - decreased binding
119
Q

Metabolism of 5-FU?

Elimination?

A

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

120
Q

How can 5-FU be administered?

A

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!

121
Q

PK of 5-FU is it linear or non-linear?

A

**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

122
Q

List the 7 toxicities associated with 5-FU?

What are the DLT?

– **Fatal in what species?

A
  • 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

123
Q

5-FU – Drug interactions

Increased toxicity is seen with what 5 drugs?

A

– 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

124
Q

5-FU Drug Interactions

Decreased toxicity is seen with what drug?

A

– Allopurinol

• Inhibits OPRT (normally activates 5-FU)

125
Q

Capecitabine

Administration?

Metabolism?

A
  • 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
126
Q

Cytosar is an analog of what?

What are the 2 MOAs?

A

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)

127
Q

How does cytosar enter the cell?

How is cytosar converted into its active form?

A

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)
128
Q

How is cytosar eliminated?

A

– Deamination

– In liver, tissues, and plasma

129
Q

What is the PK of cytosar?

Does it cross BBB?

Routes of administration?

A

Rapid disappearance from plasma d/t deamination

– Elimination t1/2 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

130
Q

List the 5 MORs for cytosar?

A
  • 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

131
Q

What are the DLT for cytosar?

Other toxicites?

A
  • 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

132
Q

Cytosar Drug Interactions

What drigs lead to increased toxicity?

A

– 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

133
Q

Gemcitabine is an analog of what?

2 main MOAs?

A

Cytosine analog

– 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
134
Q

How does Gemcutabine enter the cell?

Metabolism of cytosar?

A

hENT transported (same as cytosar)

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

135
Q

How is gemcitabine eliminated?

A

– Deamination in liver, plasms, and tissues

– Reduce dose with elevated serum bilirubin

136
Q

Gemcitabine 4 MORs?

A
  • Decreased CdR kinase
  • Increased deaminase
  • Increased ribonucleotide reductase
  • Decreased nucleoside transport
137
Q

What are the 5 main toxicites associated with Gemcitabine?

DLT for Gemcitabine?

A

• Myelosuppression – DLT

– Longer duration infusions lead to greater myelosuppression

  • GI – epithelial ulceration
  • Flu-like symptoms
  • Thrombotic microangiopathy -> hemolytic uremic syndrome
  • Pulmonary toxicity
138
Q

Gemcitabine – Interaction w/ platinums

• Why synergistic with platinum agents?

A

– 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

139
Q

Gemcitabine and carbo postamp in canine app OSA (McMahon et al, JVIM 2011)

– Synergism shown in OSA cell lines (carbo combined with low-dose gemcitabine at 2mg/kg)

– 50 patients with OSA given 300mg/m2 carbo followed by 2mg/kg gemcitabine (20 min infusion 4 hrs later)

– DFI 6.7 months, MST 9.3 months

A
140
Q

• What causes radiosensitizing properties?

– Inhibition of ribonucleotide reductase

– Leads to depletion of dNTPs and decreased DNA repair

  • Radiosensitization happens at doses well below those used for cytotoxicity
  • What are the main issues with using gemcitabine as a radiosensitizer?

– Severe local tissue toxicity

– Radiosensitizes tumor and normal tissues = narrow therapeutic window

A
141
Q

Purine Antimetabolites – 6-MP and Azathioprine

Analogs of what?

Activated by?

Metabolism?

Eliminated by what 2 enzymes?

What kind of drug is azathioprine?

A

– 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

142
Q

Purine Antimetabolites – 6-MP and Azathioprine

What is the MOA?

Cell cyle specific or non-specific?

A

– **Incorporation of metabolites into DNA and RNA -> leads to APOPTOSIS thru MMR

– Inhibits de novo purine synthesis

– S-phase specific

143
Q

Purine Antimetabolites – 6-MP and Azathioprine

Drug interactions (increased toxicity)?

WHat are the 4 toxicities associated with these drugs?

A

– 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

144
Q

Purine Antimetabolites – 6-MP and Azathioprine

What species is extra sensitive to these drugs and why?

A

Cats - have lower levels of TPMT

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

145
Q

Purine Antimetabolites – 6-TG

What is the MOA?

A

– 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
146
Q

Purine Antimetabolites - Fludarabine

Analog of?

Activated by?

Excretion?

A

• General characteristics

– Adenosine analog

– Activated intracellularly by dCd kinase to F-ara-ATP

– Renally excreted

147
Q

List 5 MOA for fludarabine?

DRug interactions?

Toxicity?

A

• 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)

148
Q
A
149
Q

Hydroxyurea MOR?

A

Elevation of ribonucleotide reductase activity

150
Q

Hydroxyurea bioavailability?

Metabolism?

Elimination?

• Crosses BBB

A

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

151
Q

Hydroxyurea toxicities? DLT?

A
  • 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

152
Q

Hydroxyurea Interactions

• Enhances cytotoxicity of purine and pyrimidine analogues

– Decreases competitive pools of triphosphates

– Synergy has been demonstrated w/ 5-FU (d/t lower dUMP pools)

• Radiosensitizer – WHY?

– Synchronizes cells in G1/S phase and depletes deoxynucleotide pools ! inhibition of DNA repair after xrt

A
153
Q

What are the 3 formulations of ELSPAR?

A

– Purified from Escherichia coli (formulation we use)

– Purified from Erwinia carotovora (chrysanthemi)

– PEGylated L-asparaginase

  • Reduced antigenicity
  • Longer t1/2
  • Used in humans when they develop hypersensitivity to E. coli or E. carotovora formulations
154
Q

Whats is L-asparaginase?

Asparagine?

Synthesized by?

A

Enzyme

non-essential amino acid

Synthesized by transamination of L-aspartic acid

  • Amino group donated by glutamine
  • Reaction catalyzed by L-asparagine synthetase
155
Q

ELSPAR

Tumor cells lack?

Hydrolysis of L-asparagine leads to?

Maximal effect seen in what phase of cell cycle?

A

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
156
Q

What are the 3 MORs for ELSPAR?

A

• 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

157
Q

Metabolism/elimination of ELSPAR?

Does it penetrate BBB?

A

– Metabolic degradation

– Immune clearance

– Does not cross BBB but depletes asparagine in the CSF

158
Q

Drug interactions with ELSPAR?

A

– 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

159
Q

Primary toxicity of ELSPAR is related to?

A

– Decreased protein synthesis

– Immunologic sensitization

160
Q

Decreased protein synthesis with ELSPAR leads to?

A

– Decreased albumin

– Decreased insulin -> hyperglycemia

– Increased serum lipoproteins and triglycerides

– Coagulation abnormalities -> decreased clotting factors and antithrombin

• Can see thromboembolism, less commonly bleeding

161
Q

• Other toxicities associated with ELSPAR?

A

– 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

162
Q
A

Chemotherapy (1 decks)

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