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Onco Board Review 2 > Chemo/Targeted > Flashcards

Chemo/Targeted Flashcards

1
Q

What effects does mCTX have on STS?

A

decreased blood vessel density, depleted Tregs (immunomodulatory)

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2
Q

What kind of T cells are Tregs?

A

CD4+

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3
Q

What is rosiglitazone?

A

peroxisome proliferator-activated receptor gamma (PPARγ) agonist and antidiabetic agent in humans

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4
Q

What supportive care medication decreases permeability of the BBB? (Chabner)

A

corticosteroids

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5
Q

What are two ways antifolates inhibit DNA biosynthesis?

A
  1. partial depletion of reduced-folate substrates

2. direct inhibition of folate-dependent enzymes

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6
Q

What does methotrexate inhibit?

A

dihydrofolate reductase (DHFR) - results in depletion of reduced folates

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7
Q

How is methotrexate transported into the cell?

A

reduced folate carrier system

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8
Q

What are 5 mechanisms of resistance to methotrexate?

A
  1. decreased transport into cell
  2. increased efflux by MDR1, MRP1, 2, 3, BCRP
  3. decreased intracellular polyglutamation
  4. decreased binding to DHFR (due to mutation)
  5. gene amplification of DHFR
  6. changes in level/affinity for thymidine synthase
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9
Q

How does L-spar affect methotrexate?

A

blocks activity (through AA deprivation)

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10
Q

How do NSAIDs affect methotrexate?

A

decrease renal clearance, increase toxicity

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11
Q

How does methotrexate affect 5-FU and Cytosar?

A

increases activity

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12
Q

How is MTX metabolized?

A
  • converted to poly glutamates within cells (by follypolyglutamyl synthetase); polyglutamated MTX retained intracellularly
  • metabolized in liver
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13
Q

How is MTX excreted?

A

excreted as intact drug in urine - dose reduce with CKD!!

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14
Q

What is leucovorin?

A

source of reduced folate - used 24-36h after high dose MTX; decreases/prevents toxicity via competition

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15
Q

What PK parameter determines efficacy of MTX? What other drugs follow this principle?

A

DURATION of exposure above threshold concentration

same for cytosar, vincas, taxanes

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16
Q

Is MTX cell-cycle specific?

A

Yes - S-phase

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17
Q

What is the MOA of 5-FU?

A

5-FU converted to FdUMP which acts to inhibit thymidylate synthase (responsible for conversion of dUMP to dTMP (a precursor of dTTP))
Other MOA:
- also converted to FUTP and incorporates in RNA
- also converted to FdUTP and incorporates in DNA

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18
Q

How is 5-FU transported into the cell?

A

shares facilitated transport with uracil, adenine, hypoxanthine

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19
Q

What are 5 mechanisms of resistance to 5-FU?

A
  1. decreased uptake (mutations in nucleoside transporters)
  2. increased efflux
  3. decreased activation
  4. increased activation by DPD
  5. mutations of thymidylate synthase
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20
Q

How do cimetidine and IFNalpha affect 5-FU?

A

decreased clearance

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21
Q

How does 5-FU interact with radiation?

A

radio sensitization through decrease in dTTP pools – inhibits DNA repair

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22
Q

5-FU inhibits metabolism of which two drugs?

A

warfarin, phenytoin

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23
Q

How does leucovorin affect 5-FU?

A

provides increased intracellular folates which augments inhibition of thymidylate synthase
(benefit seen in clinical trials but toxicity enhanced)

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24
Q

What important enzyme is involved in 5-FU metabolism? What happens if you’re deficient in this enzyme?

A

Dihydropyrimidine dehydrogenase - initial rate-limiting step in 5-FU catabolism
- DPD deficiency in people causes severe toxicity

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25
Q

What important 5-FU enzyme has been evaluated in cats? What were the findings? (Saba 2013)

A

DPD
23% had value associated with decreased DPD activity (based on human studies)
Measured U:UH2

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26
Q

How is 5-FU eliminated?

A

90% by catabolism/anabolism

<10% excreted in urine and lungs (urea, CO2)

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27
Q

How does toxicity differ between CRI and bolus of 5-FU?

A 
CRI = mucositis
Bolus = myelosuppression
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28
Q

What are the toxic and fatal doses of 5-FU in dogs?

A

> 20 mg/kg = neurotoxicity

>43 mg/kg = fatal

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29
Q

What toxicities does capecitabine cause in dogs?

A

corneal and neurotoxicity

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30
Q

What does bevacizumab target?

A

VEGF-A ligand

humanized mAb

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31
Q

What does trastuzumab target?

A

HER-2

humanized mAb

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32
Q

What is cytosar an analog of?

A

deoxycytidine (precursor of dCTP)

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33
Q

What is the rate-limiting step of cytosar metabolism?

A

Deoxycytidine kinase enzyme converts Ara-C to Ara-CMP

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34
Q

What is the active form/metabolite of cytosar?

A

Ara-CTP

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35
Q

What is the MOA of cytosar?

A

Inhibition of DNA polymerase-alpha

Ara-C becomes incorporated into DNA to cause DNA chain termination and induction of apoptosis

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36
Q

How is cytosar transported into the cell?

A

carrier-mediated process via nucleoside transporters

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37
Q

What are mechanisms of resistance to cytosar?

A
  1. decreased activation by deoxycytidine kinase
  2. increased activation by deaminases (produces inactive metabolite Ara-U)
  3. decreased drug uptake (mutation in nucleoside transporters)
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38
Q

Is cytosar cell cycle specific?

A

Yes (S-phase)

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39
Q

What PK parameter determines efficacy of cytosar?

A

duration of exposure (correlates with cell kill)

this is also the case for MTX, vincas, taxanes

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40
Q

What is the role of cytosar in canine stage V LSA? (Marconato VCO 2008)

A

dogs with bone marrow involvement treated with CHOPL and Cytosar - MST 243d (vs. 72.5 with CHOPL alone); dogs received both EPO and Neupogen

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41
Q

What is the metabolism for gemicitabine? (apparently less important than cytosar and Cytoxan)

A

dFdc is phosphorylated by deoxycytidine kinase to dFdCMP –> dFdCDP –> dFdCTP

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42
Q

Where is gemcitabine inactivated?

A

Inactivated by deaminases in the LIVER (reduce dose for liver dysfunction)

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43
Q

What is the MOA of gemcitabine? (two things)

A
  • dFdCTP is incorporated in to DNA and causes termination of chain elongation and inhibits DNA repair
  • dFdCDP inhibits ribonucleotide reductase (results in decreased deoxyribonucleotide pools necessary for DNA synthesis)
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44
Q

How is gemcitabie transported into the cell?

A

carrier-mediated transport via nucleoside transporters

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45
Q

Name 4 mechanisms of resistance to gemcitabine.

A
  1. decreased activation by deoxycytidine kinase
  2. increased activation by deaminases
  3. increased expression of ribonucleotide reductase
  4. decreased drug uptake (mutation in nucleoside transporters)
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46
Q

What is the mechanism of radiosensitization with gemcitabine?

A

inhibition of ribonucleotide reductase (results in decreased deoxyribonucleotide pools necessary for DNA synthesis)

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47
Q

What was the RR with gem/carbo for carcinomas? % GI toxicity? (Dominguez 2009)

A

RR 13% (prostatic carcinoma had a CR, GI ACA and tongue SCC had PR)
73% GI toxicity (usually mild)

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48
Q

What responses were seen with gem/carbo for feline carcinomas? What was toxicity? (Martinez-Ruzafa 2009)

A

1 CR, 1 PR

33.3% neutropenia, 16.7% thrombocytopenia, 16.7% GI dox (similar to any chemo protocol)

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49
Q

What were the results of a phase 1 study with gemcitabine in dogs? MTD, DLT, detectable in urine, tumor responses? (Marconato JVIM 2015)

A

MTD 900 mg/m2 (weekly)
DLT neutropenia
Tumor responses in TCC, mammary, primary lung

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50
Q

What is the MOA of 5-azacytidine and decitabine?

A

Inhibit DNA methyltransferase to inhibit DNA methylation and promote expression of suppressed genes
Also incorporated into DNA +/- RNA

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51
Q

What is 6-MP? What is it a structural analog of?

A

Guanine analog

Hypoxanthine

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52
Q

How is 6-MP metabolized?

A

Activated intracellularly by HGPRT (hypoxanthine guanine phosphoribosyl transferase) to TIMP – metabolized to thioguanine nucleotides which are the active products

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53
Q

How is 6-MP catabolized?

A

By xanthine oxidase and TPMT (thiopurine methyltransferase)

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54
Q

Why is genetic screening for TPMT (thiopurine methyltransferase) important in humans?

A

low activity can result in decreased drug metabolism and increased toxicity

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55
Q

What is the MOA of 6-MP?

A

incorporation of thioguanine metabolites into DNA - causes miscoding, results in apoptosis via MMR
(secondary MOA - also inhibits purine synthesis, incorporation into RNA)

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56
Q

What drug interaction is seen with 6-MP and allopurinol?

A

concurrent use causes inhibition of XO which increases 6-MP activity

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57
Q

What is the metabolism of 6-TG (thioguanine)?

A

activated to TGMP (6-thioguanylic acid) by HGPRT (hypoxanthine guanine phosphoribosyl transferase)

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58
Q

How is 6-TG catabolized?

A

By TPMT (NOT XO)

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59
Q

What is the MOA of 6-TG?

A

incorporates TGMP into DNA, triggers apoptotic with MMR

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60
Q

What were the results of 6-TG and zebularine with canine malignant lymphoid cells? (Flesner BMC Vet Res 2014)

A
  • Down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells
  • dose-dependent decrease in cell survival was also observed (apoptosis)
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61
Q

What is azathioprine’s metabolism and MOA similar to?

A

6-MP

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62
Q

What is zebularine?

A

nucleoside analog of cytidine, also inhibits DNA methylation

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63
Q

What are the uses of allopurinol?

A

prevention of hyperuricemia and uric acid nephropathy

NOT NEEDED in dogs, hyperuricemia not a problem - different pathway

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64
Q

What electrolyte abnormalities are seen in TLS?

A

increased K, increased PO4, decreased Ca
increased uric acid (due to cell destruction with release of purines from degraded DNA) - can cause renal failure due to precipitation of urate crystals in distal renal tubules

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65
Q

What is the MOA of allopurinol?

A

inhibition of xanthine oxidase (to inhibit conversion of xanthine and hypoxanthine to uric acid)

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66
Q

Name two important drug interactions with allopurinol.

A

Increases half-life of 6-mercaptopurine and azathioprine

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67
Q

How does rasburicase treat TLS?

A

recombinant urate oxidase (aka uricase - most mammals have this enzyme but humans don’t) that converts uric acid to allantoin

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68
Q

Why doesn’t uric acid accumulation occur in dogs with TLS?

A

Dogs (other than Dalmatians and English Bulldogs) oxidize uric acid to allantoin in the liver via uricase, prevents hyperuricemia.
In humans, allopurinol is indicated because purines (released from damaged cells) are catabolized by the liver through oxidation of hypoxanthine and xanthine to produce uric acid.

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69
Q

What is the main MOA of hydroxyurea?

A

inhibition of ribonucleotide reductase (rate-limiting enzyme in de novo synthesis of deoxyribonucleotide triphosphate)

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70
Q

How does hydroxyurea enter cells?

A

passive diffusion

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71
Q

Is hydroxyurea cell-cycle specific?

A

Yes, S-phase

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72
Q

How is hydroxyurea excreted?

A

renal excretion - decrease dose with renal dysfunction

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73
Q

What is the main MOR to hydroxyurea?

A

increased ribonucleotide reductase activity

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74
Q

How does hydroxyurea affect the activity of anti-metabolites?

A

increases their activity by reducing competitive pools of physiologic triphosphates

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75
Q

Which drugs should be avoided or dose reduced in patients with azotemia? (5)

A 
cisplatin
etoposide
carboplatin
bleomycin
methotrexate
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76
Q

Which drugs should be avoided or dose reduced in patients with hepatic dysfunction/hyperbilirubinemia? (8)

A 
paclitaxel
etoposide
vincristine
vinblastine
vinorelbine
docetaxel
mitoxantrone
doxorubicin
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77
Q

Which cancers have shown a PR to piroxicam as single agent? (Knapp 1992, also Eichstadt 2016)

A

TCC, TVT, SCC, mammary carcinoma

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78
Q

What cell cycle phase transition is blocked by gemcitabine?

A

G1 to S phase

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79
Q

What is the active form of gemcitabine (once it gets into cell)?

A

dFdCTP

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80
Q

What enzyme regulates the rate limiting step of gemcitabine metabolism?

A

deoxycytidine kinase (dCK)

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81
Q

What rate of gemcitabine administration is recommended in cats to achieve target plasma concentration (TPC)? (Garnett, Rodriguez 2016)

A

Fixed dose-rate between 2.5-5 mg/m2 per minute.

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82
Q

What two things does folate depletion interfere with?

A

nucleotide synthesis and DNA methylation

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83
Q

What happens when dTMP synthesis is inhibited in conditions of low folate?

A

Uracil is incorporated in to the DNA instead

Both uracil disincorporation and DNA strand breaks are observed in folate-deficient humans

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84
Q

Why does cyclophosphamide spare platelets?

A

May be due to increased aldehyde dehydrogenase in stem cells - inactivates CTX

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85
Q

What is the active form of CTX?

A

phosphoramide mustard

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86
Q

What drug type is particularly teratogenic?

A

antimetabolites

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87
Q

What are the targets of masitinib?

A

KIT, PDGFR, Lyn

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88
Q

What is bevacizumab?

A

Humanized IgG1 mAb against VEGF

treats colorectal cancer

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89
Q

What is cetuximab?

A

chimeric IgG1 mAb against EGFR

treats colorectal cancer

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90
Q

What is the difference in MOA between low and high doses of vinca alkaloids?

A

High - bind to low affinity sites (sides of microtubules), leads to tubular depolymerization and reduced microtubule mass; inhibits assembly
Low - binds to high affinity sites (end of microtubules) - disrupts dynamic processes but microtubule mass not affected

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91
Q

How are vincas transported into the cell?

A

passive diffusion

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92
Q

What is the most important determinant of cytotoxicity of the vinca alkaloids?

A

duration of exposure above a critical threshold

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93
Q

Two main mechanisms of resistance to vincas and taxanes?

A
  • increased drug efflux

- alterations in tubules that confer hyperstability

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94
Q

How do you dose vinc in patient with hepatic dysfunction?

A

At UMN:
If t.bili >2.0 – Decrease by 75%
If t.bili 0.6 – 1.9 – Decrease by 50%

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95
Q

What are 3 cytochrome p450 inducers? How do they affect vincas?

A

phenobarbital, phenytoin, rifampin, steroids

decreased VCR efficacy because increased metabolism

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96
Q

What are 3 cytochrome p450 inhibitors and how do they affect vincas?

A

erythromycin, ketoconazole, cimetidine

increase VCR toxicity because decreased metabolism

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97
Q

What are DLTs of vincas?

A

VCR: peripheral neuropathy

VBL, VRL, VFL, VDS: neutropenia

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98
Q

What endocrine toxicity is possible with vincas?

A

SIADH (hyponatremia, seizures)

also caused by CTX, cisplatin, thiazides, morphine, pulmonary/CNS infections

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99
Q

What is the proposed MOA for vinc’s ability to increase circulating PLT?

A

causes endoreduplication (replication of genome in absence of cell division) of megakaryocytes

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100
Q

MOA of taxanes? Where do they bind?

A 
inhibit depolymerization (disassembly) of tubulin
bind interior of microtubules
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101
Q

Would you expect a tumor resistant to vinc and DOX to respond to paclitaxel?

A

No - MDR1 resistance

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102
Q

How does paclitaxel interact with DOX? Cisplatin?

A

DOX - reduced clearance, increased cardiotox

CIS - given before paclitaxel reduces clearance of paclitaxel

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103
Q

What is the incidence of hypersensitivity in dogs treated with IV paclitaxel? How does Paccal Vet avoid this?

A

64% HS (Poirier JVIM 2004)
Paccal Vet is water soluble and does not have the Cremophor EL
(pretreat with steroids and H1/H2 blockers for paclitaxel)

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104
Q

What is the MTD of oral docetaxel in dogs and cats?

A

Dogs - 1.625 mg/kg with 5 mg/kg CSA q2 weeks
Cats - 1.75 mg/kg with 5 mg/kg CSA
(2.25 mg/kg in cats if IV)
- can achieve therapeutic plasma concentration at lower dose with CSA

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105
Q

MOA of epothilone B? MTD and DLT of epothilone B in dogs?

A

inhibits tubulin depolymerization
MTD 2.76 mg/m2 IV weekly
DLT was GI

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106
Q

Is there cross-resistance in taxanes?

A

No

not affected by over expression of MDR1

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107
Q

What drugs are nitrogen mustards? (alkylating agents)

A

mustargen, melphalan, chlorambucil, CTX, ifosfamide, bendamustine

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108
Q

What drugs are nitrosureas? (alkylating agents)

A

CCNU, BCNU, streptozotocin

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109
Q

Which agents are the most carcinogenic?

A

mustargen and methylating agents

110
Q

What is a monofunctional alkylating agent? Bifunctional?

A

mono- do not produce DNA crosslinks - cytotoxic effects through MMR (mismatch repair)
bi - interstrand and intrastrand DNA crosslinks which lead to inactivation of DNA template, cessation of DNA synthesis, and cell death

111
Q

Which drugs are monofunctional alkylating agents?

A

procarbazine, DTIC, CCNU

112
Q

Which drugs are bifunctional alkylating agents?

A

nitrogen mustards, BCNU, aziridines, alkyl sulfates (busulfan)

113
Q

What is present in tumor cells that are resistant to CTX?

A

ALDH (aldehyde dehydrogenase) - converts aldophosphamide to the inactive carboxyphosphamide
may also be increased expression in stem cells which is why CTX is platelet-sparing

114
Q

What are the toxicities of CTX in humans? (4)

A

myelosuppression (PLT sparing), SHC, hemorrhagic myocarditis, SIADH

115
Q

What drug is recommended for mustargen extravasation?

A

sodium thiosulfate

116
Q

What is the active metabolite of ifosfamide? What are toxicities of ifosfamide in humans? (4)

A

isophosphoramide mustard
mild myelosuppression, SHC, neurotoxicity (chloroacetylaldehyde metabolite), nephrotoxic at high doses (Fanconi-like syndrome)

117
Q

Name 3 drugs that are associated with pulmonary fibrosis? (BBB)

A

Busulfan, BCNU, bleomycin

118
Q

Regarding PK parameters - efficacy of alkylating agents is related to what?

A

AUC

119
Q

T/F: dexamethasone is an effective chemoprotectant agent in dogs receiving CCNU.

A

False - Intile VCO 2009, did not prevent myelosuppression

120
Q

What are risk factors for developing SHC in canine LSA patients?

A

increased cumulative dose (odds increase by 2.21 per 750 mg/m2), short induction protocol decreased risk

121
Q

Preferred alkylating sites of busulfan, mustargen, melphalan?

A

Busulfan - N-7 position of guanine
Mustargen - N-7 position of guanine
Melphalan - N-7 position of guanine or N-3 position of adenine

122
Q

Preferred alkylating sites of nitrosureas, procarbazine, dacarbazine?

A

Nitrosurea - O-6 position of guanine
Procarbazine - O-6 position of guanine
Dacarbazine - O-6 position of guanine

123
Q

T/F: Methylating agents are prodrugs.

A

True

124
Q

Are methylating agents mono or bifunctional?

A

monofunctional

125
Q

What is the MOA of methylating agents?

A

methylation of nucleic acids (forms O6-methylguanine)

inhibits DNA, RNA, protein synthesis

126
Q

What are the MOR to methylating agents?

A

increased MGMT-mediated repair of O6-methylguanine

MMR deficiency

127
Q

What toxicities were seen with tumor-bearing cats treated with DOX + TMZ?

A

Gagnon JFMS 2012
grade 3/4 hematologic toxicity, GI toxicity
pleural/pericardial effusions seen with higher cumulative doses of TMZ

128
Q

Why were cats in the DOX/TMZ study euthanized? (Gagnon JFMS 2012)

A

severe/prolonged myelosuppression with fever
pleural effusion
pericardial effusion
(effusions were seen in cats with higher cumulative doses of TMZ)

129
Q

When in the cell cycle are topoII inhibitors most active?

A

Late S/G2 - but not really cell cycle dependent

130
Q

What are 3 MOR against topoII inhibitors?

A
  1. efflux due to MDR1, MRP1, BCRP
  2. GSH-mediated drug inactivation
  3. decreased topoII levels
131
Q

What is the acute DLT of topoII inhibitors in people?

A

myelosuppression

132
Q

W/hat carrier can cause patients receiving etoposide to have allergic reactions? Are topoII inhibitors carcinogenic?

A

Polysorbate 80

Yes - develop AML 24-30 months after tx

133
Q

Is oral etoposide bioavailable in dogs?

A

No - Flory 2008

HS rxn to IV etoposide seen in 50% d/t polysorbate 80

134
Q

What is elsamitrucin and the results of a phase I trial?

A

topoII inhibitor
MTD was 0.08 mg/kg IV weekly
severe AEs included CHF, hepatotoxicity, severe GI, cardiac arrest (no serious AE’s at 0.08 mg/kg)

135
Q

From which two bacteria is L-spar derived?

A

E-coli and Erwinia

136
Q

What is MOA of L-spar?

A

converts asparagine to aspartic acid and ammonia

137
Q

What are 3 MOR to L-spar?

A
  1. upregulation of asparagine synthetase
  2. formulation of neutralizing AB
  3. defective induction of apoptosis
138
Q

Name 5 possible toxicities secondary to L-spar?

A
  1. decreased protein synthesis (albumin, insulin) - leads to hyperglycemia, increased lipoproteins/TG
  2. decreased pro- and anti-coagulating factors (can lead to thrombosis)
  3. HS Rxn
  4. pancreatitis
  5. cerebral dysfunction
  6. increased liver enzymes - careful with liver dysfunction
139
Q

What effect does L-spar had on vinc and MTX?

A

decreased hepatic clearance of vinc

blocks activity of MTX

140
Q

Where is ifosfamide activated?

A

Requires metabolic activation by microsomal mixed function oxidases in liver (not in the cell)

141
Q

What is the role of the ubiquitin-proteasome pathway? What are the two major components?

A

degradation of intracellular proteins

1 - ubiquinating enzyme complex, 2 - proteazome

142
Q

What is the MOA of bortezomib?

A

inhibits proteasome (boronia acid on bortezomib binds threonine on the proteasome to prevent protein degradation)

143
Q

In which two human cancers is bortezomib used?

A

MM and mantle cell LSA

144
Q

What are the 3 major effects of proteasome inhibition?

A
  1. inhibition of NFkB (transcription factor that promotes proliferation) through stabilization of IKB and prevention of NFkB translocation to nucleus
  2. induction of ER stress-mediated apoptosis by triggering unfolded protein response
  3. disruption of normal regulation of the cell cycle
145
Q

How do HDACi affect histone?

A

cause histone acetylation which increases gene expression to promote differentiation, apoptosis, and cell cycle arrest
(prevents tumor cells from silencing these genes - HDAC removes acetyl group and renders a region transcriptionally inactive)
- note that HDACi have MANY more MOA than this

146
Q

What kind of drug is valproic acid?

A

HDACi

significant growth inhibition and apoptosis in combo with DOX (Wittenburg CCP 2011)

147
Q

What is the diffusion limit of O2? What is the critical step in initiation of the angiogenic switch?

A

100uM

Activation of Hif-1

148
Q

What are the main ligand and receptor for angiogenesis?

A

VEGF-A

VEGFR2

149
Q

What is the MOA of bevacizumab? What veterinary cancer has this been studied in?

A

targets VEGF ligand

OSA - inhibited tumor growth in mice

150
Q

What are the targets of sorafenib?

A

VEGFR, PDGFR, Flt3, KIT, RET, Raf kinase

151
Q

What are the targets of sunitinib?

A

VEGFR, PDGFR, Flt3, KIT, RET, CSF-1R

152
Q

How are sorafenib and sunitinib metabolized?

A

All TKIs are CYP3A4 (cytochrome p450) metabolized

153
Q

What are the targets of toceranib?

A

VEGFR, PDGFR, Flt3, KIT, CSF-1R

154
Q

What are the targets of masitinib?

A

PDGFR, KIT, Lyn

155
Q

What are the targets of imatinib? What is its MOA?

A

BCR-ABL, PDGFR, KIT

Targets ATP binding site of the TK and fixes the enzyme in inactive conformation

156
Q

In which human cancers is imatinib used?

A

CML, GIST

157
Q

What were results of a phase I of imatinib in cats? Dose?

A

10 mg/kg q24h recommended
well-tolerated
tumor stabilization in ISS

158
Q

What were the results of imatinib in canine MCT?

A

48% RR, 10 mg/kg q24h, minimal toxicity

hepatotoxicity previously seen at 100 mg/kg

159
Q

What mutation in HER2 is seen in breast cancer?

A

amplification - associated with more aggressive phenotype

160
Q

What is the MOA of trastuzumab?

A

binds to extracellular domain of HER2

161
Q

What are the MOR to trastuzumab?

A

mutation in extracellular domain of HER2
activation of downstream signals
activation of alternative GF pathways (growth factor)

162
Q

What is the MOA of lapitinib?

A

TKI that targets HER2 and EGFR

163
Q

What is the MOA of thalidomide?

A

direct pro-apoptotic effect, inhibits protective effect of BM stroma (for MM specifically), inhibit cytokine production, anti-angiogenesis, immunomodulation (stimulates NK/T-cells)

164
Q

For which human cancer is thalidomide used?

A

MM

165
Q

In which veterinary cancers has thalidomide been studied?

A

feline OSCC (combo w/piroxicam, bleo, RT, surgery); Canine OSA xenotransplant; canine lung tumors

166
Q

What is the MOA of tamoxifen? Where is it anti- and pro-estrogenic?

A

selective estrogen receptor modulator

anti-estrogenic = breast; pro-estrogenic = bone, CV tissue, uterus, liver

167
Q

What side effects of tamoxifen were seen in dogs?

A

vulvar enlargement/discharge, attractiveness to males, nesting behavior, pyometra in intact females (Morris 1993)

168
Q

Name the steroidal hormonal treatment.

A

Fulvestrant - pure anti-estrogen

169
Q

How do steroidal and non-steroidal aromatase inhibitors work? Give examples of each.

A

Inhibit conversion of testosterone to estradiol.
steroidal = exemestane (bind aromatase and block conversion, irreversible)
nonsteroidal = anastrozole (disrupt aromatase active site without affecting steroid binding sites of others)

170
Q

How do LHRH/GnRH agonists work against breast cancer? What is the acute flare up?

A

inhibit gonadotropin secretion to inhibit estrogen production
initial increase in LH, FSH, and estrogen may cause acute exacerbation of dz

171
Q

What drugs are used in chemoprevention of prostate cancer? What is their MOA?

A

finasteride, dutasteride

inhibit 5a-reductase (converts testosterone to DHT which is most potent form of androgen)

172
Q

What was the max tolerated target AUC for a single dose of carboplatin in cats (using GFR)?

A

2.75 min•mg•mL−1

173
Q

What is the equation for calculating dose of carboplatin in cats based on GFR? (Bailey 2004)

A

Dose = AUC x 2.60 x GFR x BW(kg)

174
Q

What is the difference between topoI and topoII?

A

Both relax supercoiled dsDNA
topoI causes a ss nick in DNA while topoII causes a ds nick in the DNA – both followed by swiveling of DNA at the nicks and re-ligation

175
Q

What is the MOA of topoI inhibitors?

A

stabilize cleaved complex and prevent re-ligation

176
Q

During which cell phase are topoI inhibitors most active?

A

S-phase (but are not totally cell cycle specific)

177
Q

What is the most active metabolite of irinotecan? How is this metabolite catabolized?

A

SN-38

catabolized by UDP-glucoronyl transferase - this enzyme is highly polymorphic in the human population

178
Q

What are the major toxicities to irinotecan?

A
  • DLT - delayed diarrhea and neutropenia

- cholinergic symptoms (pre-treat with atropine)

179
Q

What are the MOA of doxorubicin (per Chabner)? (6 things)

A
  • activation of signal transduction pathways
  • DNA intercalation
  • generation of ROS
  • inhibition of topoII
  • stimulation of apoptosis
  • perturbation of cell membrane
180
Q

How do anthracyclines enter cells?

A

passive diffusion

181
Q

What interactions occur between DOX and heparin, phenobarbital, Tylenol?

A
  • heparin binds to DOX and increases clearance
  • phenobarbital increases DOX clearance
  • Tylenol diminishes hepatic reduced glutathione pools which sensitizes liver to anthracycline toxicity
182
Q

What is the mechanism of DOX cardiotoxicity?

A

free radical damage to sarcoplasmic reticulum - decreased Ca binding, disrupts electrical excitation/contraction
Seen on bx: dilation of SR, disruption of myofibrils

183
Q

What was incidence of cardiotox in dogs treated with DOX in Ratterree JAAHA 2012?

A

8%
7.4% arrhythmia, 2.1% cardiomyopathy

(Hallman - 15% high risk, 3% all comers; but it’s a 2019 paper)

184
Q

What is dexrazoxane?

A

iron chelator that prevents DOX induced lipid peroxidation and cardiotoxicity but doesn’t significantly decrease anti-tumor activity

185
Q

MOR to DOX?

A
  • efflux pumps
  • decreased topoII activity
  • up regulation of O2 free radical defense (i.e. GSH)
  • decreased sensitivity to apoptosis
  • mutation in BER (PARP)
186
Q

For DOX (regarding PK) - anti-tumor activity and myelosuppression are related to ____ while carditoxicity is related to ____.

A

AUC

Cmax

187
Q

Where is DOX excreted?

A

bile - decrease with liver dysfunction

188
Q

What is the DLT of DOX in MDR1 mutant/mutant dogs? (Gustafson JVIM 2010)

A 
GI toxicity (estimated recommended dose was 10.7 mg/m2 for gut)
dose reductions to prevent likely result in sub therapeutic concentrations
189
Q

What is the MOA of mitoxantrone?

A

DNA intercalation

inhibition of topoII

190
Q

What were the results of adjuvant mitoxantrone in cats with mammary carcinoma? What were the AEs?

A 
Cunha JFMS 2015
6 mg/m2 for 4 cycles
DFI 360d, MST 480d (1.3 yrs)
AEs: azotemia, anorexia, leukopenia, vomiting
might be nephrotoxic?
191
Q

What % of dogs experienced AE when treated with epirubicin? What % were hospitalized?

A

Marrington VCO 2012
58% AEs - prophylactic meds did not avoid
24% hospitalization
(30 mg/m2 IV or 1 mg/kg if < 10kg)

192
Q

What is the MTD and DLT of oral idarubicin in dogs?

A

Vail JVIM 2012
MTD 22 mg/m2 PO (given once)
DLT: myelosuppression
11/19 dogs with LSA responded

193
Q

How does Doxil differ from doxorubicin?

A

pegylated miposomal form - addition of multiple polyethylene glycol groups extends half-life and restricts distribution

194
Q

What unique toxicity is seen with Doxil? How can it be prevented/treated? What additional toxicity is seen in cats?

A

Poirier 2002
PPED (palmoplantar erythrodysesthesia) - Vit B6 (piridoxine); PPED shown to correlate with dose intensity
23% of cats had nephrotoxicity

195
Q

What is the MOA of bleomycin?

A

activated Fe-bleomycin-O2 complex causes DNA cleavage

196
Q

Why are skin and lungs sites of bleomycin toxicity?

A

it is degraded by enzyme bleomycin hydrolase and concentration in skin/lungs is low

197
Q

What is route of excretion of bleomycin?

A

renal (decrease with renal dysfunction)

198
Q

What unique routes of bleomycin administration have been explored in veterinary patients?

A

Kelly VCO 2010 - intralesional bleomycin for acanthomatous ameloblastoma
Spugnini JVIM 2015, Tozon JFMS 2014 - IV bleomycin in conjunction with electroporation for SCC

199
Q

Bleomycin toxicities? (3)

A

pulmonary fibrosis
desquamation
HS reaction

200
Q

What is the MOA of dactinomycin?

A

inhibition of RNA and protein synthesis

201
Q

What is the RR for DMAC? Most common AE?

A

44% CR, 28% PR (72%)

AEs: 56% thrombocytopenia, 17% neutropenia, 22% GI

202
Q

In what tumor type has mitomycin C been studied in dogs?

A

Phase I intravesicular mitomycin C in TCC
5/13 PR, 2/13 severe myelosuppression
Abbo JVIM 2010

203
Q

What drug (not a chemo) is excreted via Pgp?

A

ondansetron

204
Q

What are two non-chemo drugs that can be used to inhibit MDR and therefore possibly increase efficacy of chemo drugs?

A

verapamil

cyclosporine

205
Q

Platinum agents in which configuration are clinically active?

A

cis (not trans)

206
Q

Name the carrier ligand and leaving group for: cisplatin, carboplatin, oxaliplatin

A

cisplatin - chloride
carboplatin - carboxylate
oxaliplatin - oxalate

207
Q

How are platinum agents transported in/out of cells?

A

CTR1 (copper transporter into cell)

ATP7A and ATP7B (copper transporter out of cell)

208
Q

Are platinum agents cell cycle specific?

A

No

209
Q

How does the name of an mAb help you identify origin?

A

a. Omab = murine
b. Ximab = chimeric
c. Zumab = humanized
d. Umab = human
- Most anticancer AB have ‘tu’ or ‘tum’ in the name

210
Q

All clinically active platinum compounds form ___ DNA adducts which is responsible for their cell-killing effect.

A

bifunctional

211
Q

What specific adducts account for > 80% of total platinum-DNA damage? How are these adducts repaired?

A

N7 guanine and adenosine intrastrand adducts

Repaired by NER - if repair doesn’t occur, cell death

212
Q

Four MOR to platinums?

A
  1. altered cellular accumulation of drug
  2. cytosolic inactivation (happens to alkylators, too) - by GSH, metallizedothionein, and proteins with high levels of sulfhydryl groups
  3. altered DNA repair (happens to alkylators, too) - such as increased NER, decreased MMR
  4. resistance to apoptosis
213
Q

Main/important toxicity of: cisplatin, carboplatin, oxaliplatin?

A

Cisplatin: nephrotoxic, emetogenic, ototoxic
Carboplatin: BM suppression
Oxaliplatin: cumulative peripheral neurotoxicity

214
Q

T/F: Cisplatin displays extensive long-term protein-binding in many tissues.

A

True

215
Q

Regarding PK parameters, the efficacy and toxicity of cisplatin directly relates to ____.

A

AUC

216
Q

What is the effect of lithium carbonate on carbo-induced thrombocytopenia in dogs?

A

can increase neu and PLT by unknown mechanism

no difference seen in dogs with/without lithium

217
Q

Satraplatin in tumor-bearing dogs? MTD? DLT? (Selting JVIM 2011)

A

MTD: 35 mg/m2
DLT: myelosuppression - PLT before neuts!
41% bioavailable

218
Q

Results of giving CTX by three different routes to cats? (Stroda 2017)

A

tolerated regardless of administration type

AUC was lower for oral compared to IV or IP

219
Q

How did neutropenia from FDA lomustine compare to compounded? (Burton JVIM 2016)

A

All dogs neutropenic from FDA
Only 25% neutropenia after compounded
potency from 5 compounding pharmacies ranged from 50-115%

220
Q

What is the highest inadvertent CTX dose that a dog recovered from? (Finlay 2017)

A

2,303 mg/m2 over 21d

221
Q

What % of dogs tend to have ELE on CCNU? How did Denamarin affect this percentage? (Skorupski JVIM 2011)

A

86% of dogs on CCNU with ELE

In this study, CCNU alone - 84%, with Denamarin - 68%

222
Q

What unique AE has been reported with high cumulative CCNU in a cat? (Skorupski 2008)

A

pulmonary fibrosis

223
Q

SHC in dogs with Cytoxan - what % with furosemide had it vs. no furosemide? (Charney 2003)

A

9% w/out
1.2% with
(pretty sure this was bolus dosing)

224
Q

Does metronomic temozolomide affect Tregs? (Denies 2016)

A

Not alone, Tregs decreased with mTMZ/CTX combo

225
Q

What CRs were seen with metronomic chlorambucil? (Leach 2011)

A

MCT, STS, thyroid, HiSa

226
Q

What is the dose recommended for mCTX? What effects seen in tumors? (Burton 2011)

A

15 mg/m2 daily (was compared to 12.5 mg/m2)

decreased Tregs and decreased MVD in tumors

227
Q

How does 1 mg/kg compare to 25 mg/m2 in cats with DOX? (Reiman 2008)

A

neuts significantly lower at 25 mg/m2 but tolerated

228
Q

What is suramin? Results with DOX in phase I? (Kosarek 2006)

A

naphthalene anti-parasitic; nonspecific inhibitor of multiple growth factors including FGFs
improved response in 5 dogs who had DOX alone previously

229
Q

What was MTD of idarubicin in dogs? DLT? What is idarubicin? (Vail 2012)

A

22 mg/m2
DLT: hematologic
anthracycline

230
Q

What is elsamitrucin? MTD? DLT? (Fiocchi 2011)

A

potent topoII inhibitor
0.08 mg/kg IV weekly
AEs that limited dose: cardiac arrest, severe diarrhea, severe anorexia (1 dog developed heart failure and hepatotoxicity at lower dose)

231
Q

Did furosemide help prevent SHC in dogs with mCTX? (Setyo 2017)

A

Yes
SHC in 30% of dogs not getting furosemide and 10% of dogs who did get it
(21.7% total developed SHC in this retrospective)

232
Q

Which drugs are NOT affected by Pgp?

A

alkylating agents, antimetabolites, platinums

233
Q

Which ABC transporter was associated with resistance in T cell LSA? (Zandvliet 2015)

A

ABCG2

ABCB1 in B cell

234
Q

Gemcitabine MTD and DLT? (Marconato 2015)

A

MTD 900 mg/m2

DLT neutropenia

235
Q

What unique toxicity did capecitabine cause in dogs?

A

corneal toxicity (superficial keratitis)

236
Q

How were AE affected by prophylactic TMS with DOX? (Chretin 2007)

A

Dogs with TMS had reduced hospitalization, non-hematologic toxicity, GI toxicity, and reduced altered performance
(concluded that TMS reduced morbidity)

237
Q

How did maropitant help with cisplatin induced emesis? (Vail 2007)

A

maropitant pre-med resulted in 94.9% of patients not vomiting compared to only 4.9% of controls

238
Q

What is survivin? How did inhibitor affect LSA and OSA in vitro? (Thamm 2016)

A

inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis
inhibited growth, induced apoptosis, enhanced chemrsensitivity in vitro

239
Q

MTD of pegylated TNFa? DLT? (Thamm 2010)

A

26.7 ug/kg

DLT vascular leak and coagulopathy/hypotension

240
Q

Why can cyclosporine help achieve lower doses of docetaxel?

A

docetaxel substrate of Pgp and metabolized by CYP3A
CSA modulates Pgp and CYP3A
docetaxel alone bioavailability 20% but approaches 100% with CSA

241
Q

MTD of VBL? (Bailey 2008)

A

3.5 mg/m2

neutropenia, sepsis, 1 death at this dose

242
Q

MTD and DLT of carbo in cats? (Kisseberth 2008)

A

MTD 240 mg/m2

DLT neutropenia

243
Q

MTD of metformin in cats? (Wypij 2015)

A

10 mg/kg q12h

DLT mild/moderate GI

244
Q

How long were vinc, VBL, DOX, and CTX residues detected in urine after tx in dogs? (Knobloch 2010)

A

CTX - directly after tx but not subsequent days
Vinc - 3 days
VBL - 7 days
DOX - 21 days

245
Q

What is the risk of exposure to chemo in blood samples 1 week after treatment? (Knobloch 2010)

A

Low risk, very few samples had detectable drug

246
Q

How does Palladia cause PLN?

A

VEGFR inhibitors cause loss of healthy, fenestrated glomerular capillaries and possible disruption of podocyte integrity

247
Q

How does Palladia cause hypertension?

A

VEGFR inhibition, increased endothelin-1

248
Q

Masitinib dosing in cats? AE? (Daly 2011)

A

study did 50mg EOD vs. daily for 4 weeks

10% developed proteinuria, 15% neutropenia

249
Q

Are patients <15 kg at increased risk for mitoxantrone neutropenia? (Richardson 2018)

A

Yes - and 46% of the patients developing neutropenia were hospitalized

250
Q

What is Tavocept? How did it affect required diuresis in dogs with bladder tumors? (Henry 2018, Flesner on this paper)

A

dimesna - used in humans to decrease cisplatin toxicity

In dogs, less nephrotoxicity than historic controls and decreased diuresis time from > 6hr to 90 min

251
Q

What tumors showed response to hyaluronan-cisplatin nanoconaugate? (Can 2018, Flesner on paper)

A

SCC (3/7 had CR - both oral and nasal SCC)

252
Q

What toxicity was seen with Palladia in cats? (Harper 2017)

A

10/14 - mild myelosuppression or GI effects
2 cats developed severe hepatotoxicity
1 cat developed CHF/death

253
Q

5 toxicities to Palladia in cats.

A

thrombocytopenia, neutropenia, azotemia, hepatotoxicity, GI upset

254
Q

MTD of CCNU with Palladia? DLT? ORR? (Pan 2014)

A

MTD of CCNU - 50 mg/m2 (with 2.75 mg/kg EOD Palladia)
DLT - neutropenia
ORR - 38.4%

255
Q

What was elevated in serum of dogs receiving toceranib and CTX? (Mitchell 2012)

A

IFN-gamma, inversely correlated with Treg

256
Q

Masitinib resulted in chemosensitization of HS to ____ and OSA and mammary CA to ____ and several other cancer cell lines too ____. (Thamm paper)

A

HS - VBL
OSA/mammary - Gem
others - DOX

257
Q

How did masitinib reverse DOX resistance? (Zandvliet 2013)

A

Inhibit Pgp

258
Q

What solid tumors showed clinical benefit from Palladia? (London 2011)

A 
AGASACA (88%)
OSA (48%)
Thyroid (80%)
Head/neck (SCC) (88%)
Nasal carcinoma (71%)

Given at 2.8 mg/kg MWF

259
Q

MTD of VBL with toceranib? Response rate? (Robat 2011)

A

VBL 1.6 m/m2 q2 weeks
toceranib was at 3.25 mg/kg EOD
Response rate 71%

260
Q

What unique side effect has been reported with hydroxyurea? (Conrado 2017)

A

macrocytosis

megaloblastic changes have been reported in multiple species with hydroxyurea

261
Q

What was the overall prevalence of ALT elevations in dogs with CCNU? How many dogs developed clinical hepatopathy? What breed was at 6.0x greater risk than others? (Hosoya 2009)

A

29%
Three dogs (2.8% developed clinical hepatopathy)
Boxers at greater risk in this study

262
Q

In the 2018 consensus statement, how many days after administration were the following drugs detected in urine?

  • carboplatin
  • CTX
  • DOX
  • VBL
  • vincristine
A
  • carboplatin: 21d (also looked at feces, alive, sebum, cerumen)
  • CTX: 1-4d
  • DOX: 21d
  • VBL: 7d
  • vincristine: 3d
263
Q

How does 6-TG cause genomic demethylation?

A

reduction of DNMT1 protein through the ubiquitin-proteasome pathway

264
Q

What was the biologic activity for Toceranib in the solid tumors publication? What was the objective response rate? (London 2013)

A

biologic: 74% - most SD
objective: 31.7%

265
Q

Which tumors experienced a PR in the toceranib and coli tumors paper? (London 2013)

A 
AGASACA - 25% PR
thyroid carcinoma - 26.7%
head and neck carcinoma - 62.5% PR and 12.5% CR
OSA - 4.3%
Nasal carcinoma - 14% (1/7) CR
266
Q

What toceranib targets have been identified in AGASACA and thyroid CA? Where in the cell/tumor are they expressed?

A

intracellular PDGFR-a in both
stromal PDGFR-B in both
intracellular VEGFR2 in both

267
Q

What was biologic activity of TOC/VBL? (Robat 2011) How does this compare to single agent VBL and TOC?

A

Combination - 71% (2 CR, 8 PR)

Alone: VBL - 12%, TOC - 43%

268
Q

What % of dogs develop proteinuria with toceranib? (Tjostheim and Piscoya)

A

20% in these two retrospective studies

269
Q

Which is not a mechanism of bortezomib?

a. induction of unfolded protein response
b. inhibition of NFkB pathway
c. generation of ROS
d. demythylation of transcription factors

A

D

270
Q

Which alkylating agents cross the cell membrane via active transport?

  • mustargen
  • chlorambucil
  • carmustine
  • melphalan
A

mustargen and melphalan

271
Q

What specific adducts account for the majority of platinum-DNA damage?

A

N-7 guanine and adenine intrastrand adducts

Onco Board Review 2 (20 decks)

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