Chemotherapy Flashcards
What is half-life?
Time required for plasma concentration to decrease by ½
When the amount of drug coming equals the amount of drug going out?
Steady state
What is C0 (or Css)?
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
What is Cmax?
peak plasma concentration
What is bioavailability?
Amt of drug available after PO administration/amt available after IV admininstration
What is CL?
Drug clearance (= dose given IV/AUC)
Volume of plasma from which the drug is completely removed per unit of time
What is Vd?
Related to what?
A large volume of distribution represents what?
Volume of distribution
Relates total amount of drug in the body to plasma concentration
Extensive tissue binding
What is linear PK?
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
What is non-linear PK?
Exponential characteristics at low doses and downward curvature at high doses
Clearance decreases as dose increases
What does bolus injection accomplish?
For what kind of drugs?
Provides maximum peak level
Good for cell-cycle non-specific drug
What does CRI accomplish?
Good for what kind of drugs?
Provides duration of exposure above a threshold concentration
Good for cell-cycle specific drugs
What are the 3 classes of anti-mitotic (antimicrotubule) drugs?
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
Vinca alkaloids are derived from what?
Pink periwinkle plant (Catharanthus roseus)
General structure of vinca alkaloids?
Dihydroindole nucleus (vindoline) = major alkaloid in the periwinkle plant
Linked to indole nucleus (catharanthine) = found in smaller quantities in periwinkle plant
Differences between vinca alkaloids
VCR and VBL? what groups?
VRL? Unique property?
Tubulin-binding affinities
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)
What is the microtubule structure?
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
Microtubule structure has 2 ends (treadmilling)
Minus versus plus?
Minus - α-tubulin exposed, assembly slow = net shortening
Plus - β-tubulin exposed, assembly fast = net elongation
Microtubule function
Principle component of what? What does it do?
Other improtant functions?
Other roles?
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
MOA of vinca alkaloids
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
How does different concentrations of vinca alkaloid work?
Lower concentrations –> inhibits assembly of MTs
Higher concentrations –> binds along sides of MTs leading to disintegration
What are some other effects of vinca alkaloids?
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
4 MOR for vinca alkaloids?
MDR (Pgp/MDR1 and MRP1)
Alterations in α and β subunits of tubulin
Increased expression of microtubule associated proteins (MAPs)
Alterations in apoptotic pathway
PK of vinca alkaloids (list 4)
Metabolized by what?
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
Toxicity of Vinca Alkaloids
What is DLT for vbl/vrl?
What is DLT for vcr?
4 other toxicities?
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
Vinca alkaloid is a ____?
What do you do if they extravasate?
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
3 drug interactions for vinca alkaloid?
ELSPAR –> Reduces hepatic clearance of vcr
Methotrexate –> Vinca alkaloids block efflux leading to increased intracellular accumulation
Cytochrome P450 inhibitors –> Increases toxicity of vinca alkaloids
Taxanes are derived from what?
What are the 2 drugs and if naturally occuring or synthethic and vehicle?
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)
Main MOA of Taxanes?
How do they work at high and low concentrations?
How does this differ form vinca alkaloids?
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
Taxanes lead to mitotic block at ?
MT disruption induces?
Specific for what phase?
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
List 6 other effects of taxanes?
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
3 MOR of taxanes
MDR (MDR1 and MDR2)
Alteration in tubulin binding sites
Decreased apoptosis d/t altered cell signaling
PK of taxanes
Metabolism?
4 other characteristics?
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
What is the oral bioavailability of taxanes poor?
How can you increase oral absorption?
– 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
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
DLT of taxanes?
2 other toxicities
neutropenia (3-5 day nadir)
Type I hypersensitivity (to carrier molecule), GI rare
Toxicities with Paclitaxel
–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
Toxicities with Docetaxel
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)
List 5 nitrogen mustards?
List 4 nitrosureas?
Other?
Methylating agents?
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)
MOA of alkylating agents?
Where do the drugs atttack?
Nitrogen mustards?
Nitrosureas?
Methylating agent?
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
How do alkylating agents enter cells?
What 2 drug are different?
List 2 MOAs?
Cell cycle specic or non-specific?
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
What is a bifunctional alkylating agent? Examples?
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
How is damage caused by mono-functional alkylating agents repaired?
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
Other mechanisms of repair for alkylating agents?
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
Cyclophosphosphamide
Bi- or mono functional? targets?
Metabolism?
Ifosfamide?
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
PK of oral and IV cyclophosphamide in dogs with LSA (Warry et al JVIM 2011)
Drug exposure to cyclophosphamide after IV significantly higher than PO
– First past elimination through the liver
No significant difference in exposure to 4- OHCP
What is unique about cyclophosphamide?
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
Cyclophosphamide/Ifosfamide - PK
List 3
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
Cyclophosphamide/Ifosfamide - Toxicity
What is the DLT?
List 7 other toxicities?
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
Mutargen is derived from?
Metabolism?
Mustard gas
Metabolized in plasma, excreted in urine
Alkylating agents - MOR
- 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
Alkylating agents - Mechanisms of decreasing resistance
- 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)
4 Platinum agens?
Cisplatin • Carboplatin • Oxaliplatin • Satraplatin
What is the structure of Platinum agents?
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)
PK differences of platinum agents is due to?
Cisplatin?
Carboplatin?
Oxaliplatin?
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
What is Platinum Agents - MOA
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)
Pltainum agents MOA
GpG adduct?
ApG addufct?
GpXpG adduct?
Interstand?
60%
30%
10%
<2%
What do the adducts do when formed by Platinum agents?
Cell cycle specific or non-specific?
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
Platinum Agents- Synergistic/Additive effects
Cisplatin is synergistic with?
Oxaliplatin synergistic with?
List 2 additive effects?
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)
Platinum Agents – Differences
List 4 characteristics for cisplatin
How is carbo dosed?
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
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
How do Platinum drug enter/exit cells?
Metabolism?
Elimination?
Diffusion
Active transporters (copper pumps – CTR1, ATP7A, ATP7B)
Inactivated in the bloodstream/cells by conjugation to sulfhydryl groups
90% eliminated in urine
4 MOR for Platinum agents?
- Altered cellular accumulation - Inactivation of CTR1 and Increased efflux by ATP7A/B
- Cytosolic inactivation of drug - Via glutathione, metallothionein
- Altered DNA repair - Increased NER -> **NER responsible for repair of platinumDNA damage (repairs bulky adducts). Increased ERCC1 (NER gene)
- Resistance to apoptosis - Decreased MMR ! can’t link unrepaired DNA damage to apoptotic pathways. Defective MMR proteins (p53, bcl, bax)
Platinum Agents - Toxicity
Cisplatin?
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
List 7 other toxicities associated with Platinum agents?
DLT for carbo?
- 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
List 3 Topoisomerase I inhibitors?
Camptothecin – Topotecan – Irinotecan
What are the 3 categories of Topoisomerase II inhibitors and list the individual drugs?
ANTHRACYCLINES
- Doxorubicin • Daunorubicin • Idarubicin • Epirubicin
ANTHRACENEDIONES
- Mitoxantrone
EPIPODOPHYLLOTOXINS
- • Etoposide (VP-16) • Teniposide (VP-26)
What is topoisomerase?
What is the difference between topo I and II?
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
General MOA for Topisomerase Inhibitors?
– Bind and stabilize DNA/topo cleavable complex - prevents religation
– Irreversible damage results when advancing replication fork encounters complex
• Lethal ds breaks = cell death
Topoisomerase I inhibitors - MOA
What is the “Cleavable complex”?
Interferes with what 4 processes?
Most effective in what phase?
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
Topotecan is similar to what drug?
Metabolism?
Excretion?
List 5 toxocities and what is DLT?
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
Metabolism of Irinotecan?
Toxicity? DLT?
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
List the 3 MOR for Topoisomerase I inhibitors
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
What are Anthracyclines?
Naturally occuring?
Doxorubicin analogues?
Antitumor antibiotics derived from Streptomyces bacterium
doxorubicin, daunorubicin
epirubicin, idarubicin
List 3 MOA for Anthracyclines?
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
How do anthracycline create free radicals?
Quinone ring metabolized to semiquinone radical
- Formed by one electron reduction
Main mechanism of cardiotoxicity
Note: two electron reduction = pathway of drug inactivation
The generation of free radicals by anthracyclines leads to what 4 effects?
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
Anthracycline damages cell mmembranes by what 2 ways?
Binds phospholipids via iron chelation
Activates sphingomyelin pathway • Formation of ceramide ! activates PKC ! activation of proapoptotic caspases ! apoptosis
Anthracyclines also stimulate apoptosis how?
Other MOA?
Cell cycle specific or non-specific?
Via alterations in cell membrane, DNA damage, free radical formation
Induces cellular senescence – Antiangiogenic effects – Targets tumor stem cells
NON-SPECIFIC
List 5 MOR for Anthracyclines?
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
Anthracyclines and Iron
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
Anthracyclines - Metabolism
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
Anthracyclines – PK parameters
Protein bound?
Excretion?
Antitumor effects are proportional to? Cardiotoxicity?
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
List 6 toxicities associated with Anthracyclines?
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
Treatment for extravasation for Anthracyclines?
– Ice area – Dexrazoxane – DMSO – Vitamin E – Steroids
Anthracyclines – Cardiotoxicity
Acute?
Chronic?
Increased risk at what dose?
Lesions on histopathology early and late phase?
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
Anthracyclines – Mechanisms of Cardiotoxicity
List 5 oxidative mechanisms?
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
Anthracyclines – Mechanisms of Cardiotoxicity
List 5 nonoxidative mechanisms?
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
Why is the heart particularly sensitive to anthracyclines?
Low levels of cardiac catalase
Leaves glutathione peroxidase as only pathway for hydrogen peroxide detoxification
DEXRAZOXANE (Zinecard) – What is this drug and how does it work?
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
Specific Anthracyclines
Daunorubicin?
Doxorubicin?
Idarbucin?
Epirubicin? DLT?
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
What is Doxil?
What does pegylation do?
Pegylated liposome-encapsulated doxorubicin
Extends t1/2 (by 40x), Limits distribution, Less BM toxicity and cardiotoxicity
What is a specific toxicity of Doxil and how is this treated?
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
Anthracenediones - Mitoxantrone
MOA?
Elimination?
MOR?
List 5 toxicities? DLT?
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
Epipodophyllotoxins
Derived from?
MOA?
Excretion?
Etoposide can be adminitered how?
List 5 toxicities? DLT?
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
List the 3 antifotales?
Methotrxate - folic acid analog (antifolate)
Direct thymidylate synthase inhibitors
- Raltitrexed
- Premetrexed
Nucleoside Analogs include?
List the pyrimidine analogs?
Pyrimidine and purine analogs
Pyrimidines (C, U, T)
- 5-FU - inhibit thymidylate synthase
- Capecitabine - inhibit thymidylate synthase
- Cytosar - cytidine analog
- Gemcitabine - cytosine analog
List the 4 purine analogs?
Purine (A,G)
- 6-mercaptopurine (6-MP) - guanine analog
- 6-mercaptopurine (6-MP) - guanine analog
- Azathioprine - guanine analog
- Fludarabine ! adenosine analog
How to antimetabolites function?
Cell-cyle specific or non-specific?
Toxicity?
Efficacy depends on?
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
What is the MOA for Methotrexate?
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
Another mechanism of action for Methotrexate?
Depletion of dTMPs (thymidine monophosphate) and
purines by polyglutamated forms of methotrexate
– Leads to decreased DNA synthesis -> DNA strand breaks ->
apoptosis
How does DHFR work?
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
How does methotrexate metabolism enhance DHFR inhibition?
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
What are the 3 mechanisms of uptake of Methotrexate into cells (3 mechanisms)?
– 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
Polyglutamation of MTX is mediated by?
folylpolyglutamyl synthetase (FPGS)
Inhibition of DHFR?
Depletion of dTMPs and purines -> decreased DNA synthesis -> DNA strand breaks and S->G2 arrest -> APOPTOSIS
Optimal binding depends on NADPH and PG-MTX
List 4 MOR for Methotrexate?
• Mutations in RFC or DHFR
– MTX can’t bind to either
- Increased MRP-1(2,3) and BCRP
- Defects in polyglutamation
- Increased DHFR concentrations
How is Methotrextae metabolized?
Elimination?
• Does this drug cross BBB?
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)
What are the toxicities associated with methotrexate?
DLT?
- Myelosuppresion (DLT)
- GI/mucositis (DLT)
- Renal (w/ high doses)
- Hepatotoxicity (fibrosis w/ long term use)
- Neurotoxicty
- Pneumonitis (self-limiting)
- Hypersensitivity
What are the 3 drug interactions with methotrexate?
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
PK factors for methotrexate? Which one is more important?
What 2 factors reduce cytotoxicity?
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
What is a drug that rescues patients from MTX-induced cytotoxicity?
Drugs MOA?
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
What is thymidylate synthase?
Needs what to function?
Converts dUMP to dTMP (thymidine monophosphate)
Requires cofactor 5,10-methylene-tetrahydrofolate
dTMP -> is phosphorylated to thymidine triphosphate for DNA repair and synthesi
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?
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
3 main MOAs for 5-FU?
– **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
What are the different effects of of 5-FU with regards to cell cycle?
Inhibition of TS = inhibition of DNA synthesis
• Cell cycle specific (s-phase)
– Inhibition of RNA processing, function, and translation
• Cell cycle non-specific
5-FU is phosphorylated after entering cells and becomes:
– 5-FUTP - incorporated into RNA
– 5-dUTP - incorporated into DNA
– 5-FdUMP - inhibits TS
3 MORs for 5-FU?
- Decreased activity of activating enzymes
- Increased nucleotide pool size
- Overexpression of mutation of TS - decreased binding
Metabolism of 5-FU?
Elimination?
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
How can 5-FU be administered?
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!
PK of 5-FU is it linear or non-linear?
**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
List the 7 toxicities associated with 5-FU?
What are the DLT?
– **Fatal in what species?
- 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
5-FU – Drug interactions
Increased toxicity is seen with what 5 drugs?
– 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
5-FU Drug Interactions
Decreased toxicity is seen with what drug?
– Allopurinol
• Inhibits OPRT (normally activates 5-FU)
Capecitabine
Administration?
Metabolism?
- 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
Cytosar is an analog of what?
What are the 2 MOAs?
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)
How does cytosar enter the cell?
How is cytosar converted into its active form?
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)
How is cytosar eliminated?
– Deamination
– In liver, tissues, and plasma
What is the PK of cytosar?
Does it cross BBB?
Routes of administration?
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
List the 5 MORs for cytosar?
- 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
What are the DLT for cytosar?
Other toxicites?
- 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
Cytosar Drug Interactions
What drigs lead to increased toxicity?
– 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
Gemcitabine is an analog of what?
2 main MOAs?
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
How does Gemcutabine enter the cell?
Metabolism of cytosar?
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
How is gemcitabine eliminated?
– Deamination in liver, plasms, and tissues
– Reduce dose with elevated serum bilirubin
Gemcitabine 4 MORs?
- Decreased CdR kinase
- Increased deaminase
- Increased ribonucleotide reductase
- Decreased nucleoside transport
What are the 5 main toxicites associated with Gemcitabine?
DLT for Gemcitabine?
• Myelosuppression – DLT
– Longer duration infusions lead to greater myelosuppression
- GI – epithelial ulceration
- Flu-like symptoms
- Thrombotic microangiopathy -> hemolytic uremic syndrome
- Pulmonary toxicity
Gemcitabine – Interaction w/ platinums
• Why synergistic with platinum agents?
– 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
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
• 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
Purine Antimetabolites – 6-MP and Azathioprine
Analogs of what?
Activated by?
Metabolism?
Eliminated by what 2 enzymes?
What kind of drug is azathioprine?
– 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
Purine Antimetabolites – 6-MP and Azathioprine
What is the MOA?
Cell cyle specific or non-specific?
– **Incorporation of metabolites into DNA and RNA -> leads to APOPTOSIS thru MMR
– Inhibits de novo purine synthesis
– S-phase specific
Purine Antimetabolites – 6-MP and Azathioprine
Drug interactions (increased toxicity)?
WHat are the 4 toxicities associated with these drugs?
– 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
Purine Antimetabolites – 6-MP and Azathioprine
What species is extra sensitive to these drugs and why?
Cats - have lower levels of TPMT
Certain humans w/ genetic deficiency of TPMT will have increased toxicity (screening tests available)
Purine Antimetabolites – 6-TG
What is the MOA?
– 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
Purine Antimetabolites - Fludarabine
Analog of?
Activated by?
Excretion?
• General characteristics
– Adenosine analog
– Activated intracellularly by dCd kinase to F-ara-ATP
– Renally excreted
List 5 MOA for fludarabine?
DRug interactions?
Toxicity?
• 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)
Hydroxyurea MOR?
Elevation of ribonucleotide reductase activity
Hydroxyurea bioavailability?
Metabolism?
Elimination?
• Crosses BBB
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
Hydroxyurea toxicities? DLT?
- 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
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
What are the 3 formulations of ELSPAR?
– 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
Whats is L-asparaginase?
Asparagine?
Synthesized by?
Enzyme
non-essential amino acid
Synthesized by transamination of L-aspartic acid
- Amino group donated by glutamine
- Reaction catalyzed by L-asparagine synthetase
ELSPAR
Tumor cells lack?
Hydrolysis of L-asparagine leads to?
Maximal effect seen in what phase of cell cycle?
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
What are the 3 MORs for ELSPAR?
• 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
Metabolism/elimination of ELSPAR?
Does it penetrate BBB?
– Metabolic degradation
– Immune clearance
– Does not cross BBB but depletes asparagine in the CSF
Drug interactions with ELSPAR?
– 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
Primary toxicity of ELSPAR is related to?
– Decreased protein synthesis
– Immunologic sensitization
Decreased protein synthesis with ELSPAR leads to?
– Decreased albumin
– Decreased insulin -> hyperglycemia
– Increased serum lipoproteins and triglycerides
– Coagulation abnormalities -> decreased clotting factors and antithrombin
• Can see thromboembolism, less commonly bleeding
• Other toxicities associated with ELSPAR?
– 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
