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Quick Reivew Flashcards

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1
Q

CYP450 chemo drugs

A

Cytoxan
Ifosfamide
DTIC
Procarbazine

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2
Q

Drugs that cross BBB

A

CCNU
DTIC
procarbazine
Temozolomide
Methotrexate
Cytosar

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3
Q

Drugs requiring active transport + transporter

A

Mustargen = choline
Melphalan = leucine
Streptozotocin = GLUT2
Antimetabolites = methotrexate (folate carrier), 5-FU, Cytosar, Gemcitabine = nucleoside transporters
Carbo/cisplatin = copper transporters (CTR1)

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4
Q

Carbo resistance mechanisms

A
  • Decreased uptake (via copper transporters —> CTR1 = influx; ATP7A, ATP7B = efflux)
  • Cytosolic inactivation via glutathione and metallothionine conjugation, sulfhydryl groups
    -↑NER/DSB repair, defective MMR
  • Resistance to apoptosis (MMR proteins, p53, Bcl/Bax)
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5
Q

TOPI inhibitors

A

Camptotecins = topotecan, irinotecan
Idenoisoquinoline (new)

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6
Q

TOPII inhibitors

A

Anthracyclines = doxo, dauno, epi, ida (DDEI)
Epipodophyllotoxins = topotecan/etoposodie, teniposide
Others: elsamitrucin, chartreusin, fluoroquinolones

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7
Q

ABCB1 substrates

A

**think natural things

Doxo - dauno comes from Streptomyces spp
Etoposide p comes from mandrake plant
Actinomycin D - from Streptomyces
Methotrexate - folate analog
Taxanes (paclitaxel, docetaxel) - from yew tree
Vincas - from periwinkle plant

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8
Q

MOA of doxo

A
  • DNA intercalation & inhibition of RNA and DNA pol
  • inhibition of topo II
  • alkylation of DNA
  • ROI generation
  • perturbation of Ca
  • inhibition of thioredoxin reductase
  • interaction with membrane proteins
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9
Q

Mechs of resistance for doxo

A
  • Pgp efflux
  • altered ROS intermediates
  • overexpression of Bcl-2 or decreased p53
  • increased TOPII activity
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10
Q

Dox cardiotox results from

A

Disruption of myofibrils and damage/dilation to sarcoplasmic retriculum —> oxidative damage to lipid membrane impairs its ability to bind calcium

High risk breeds = 15%
Low risk 3%
Overall 4%

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11
Q

HDACi

A

Valproic acid

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12
Q

Horse dox dose and DLT

A

70mg/m2
Hypersensitivity rxns and neutropenia

Hypersensitivity was dose dependent but schedule invariant

ORR 47%

Melanoma does not respond

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13
Q

What chemo drugs are highly protein bound

A

Doxorubicin
Mitoxantrone
Cisplatin (NOT Carbo)

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14
Q

Vesicants

A

Vincas - disperse + warm pack; hyaluronadase?
Dox - cold pack, aspirate back, dexrazoxane
Mustargen - sodium thiosulfate
Actinomycin D

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15
Q

Irritants

A
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16
Q

Prodrugs + their active metabolite

A

Cytoxan —> phosphoramide
Ifosfamide —>
Procarbazine —> MTIC
DTIC —> MITC
5-FU —> FdUMP
Cytosar/Ara-C —> dCMP *enzyme deoxycytidine kinase (rate limiting step of activation)
Gemcitabine —> dGemCDP/dFdCDP *inhibitis ribonucleotide recuctase

Tanovea —> PMEGpp (remember this is DOUBLE prodrug)

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17
Q

Drug that decreases MTX efficacy and drug that is used for MTX rescue

A

Elspar decreases efficacy
Leucovorin = MTX rescue

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18
Q

Chemo drugs you can’t use in cats

A

5-FU = fatal neurotoxicity
Cisplatin = fatal pulmonary edema

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19
Q

What drug increases sensitivity to 5-FU

A

Leucovorin

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20
Q

What drugs does 5-FU synergize with

A

MTX
Cytoxan
Anthracyclines
Platinums

And RT

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21
Q

What drug increases efficacy of Cytosar and what drugs does Cytosar enhance the activity of

A

MTX increases Cytosar efficacy

Cytosar increases alkylating and platinums efficacy

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22
Q

Gemcitabine is synergistic with what drugs

A

Platinums

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23
Q

How does Gemcitabine interact with RT

A

Radiosensitizzer

Inhibits ribonucleotide reductase and DNApol

Particularly evident in cells deficient in MMR as the analogs are ID’d as mismatch lesions in the DNA

Give 24-48h prior to RT for best effect
RT will enhance gem toxicity

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24
Q

MOA of Tanovea

A

Double prodrug

Hydrolysis by cathepsin A —> delaminating by N6-methy-AMP aminohydrolase to PMEG —> PMEG phosphorylated into PMEGpp

PMEGpp inhibits DNApol to inhibit DNA synthesis and repair

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25
Tanovea AEs
Dermatopathy 20-25% Pulmonary fibrosis 4% (2-18% depending on study)
26
MOA of taxanes vs vincas
Taxanes = stabilize microtubule against depolymerization —> inhibits reorganization and cell division during M phase Vincas = bind to positive end of Beta-tubulin to prevent microtubule formation
27
Binding affinity of vincas
VCR > VBL > VRL > VFL
28
Radiosensitizers
Gemcitabine Vincas - blocks in G2/M phase
29
MOA for platinums
Divalent inorganic complexes that are highly water soluble and readily activated by displacement of their leaving groups Form intrastrand abducts via purines (N7 guanine on A and G) - G>>>A
30
Patients with __ or __ deficiencies are very susceptible to platinum drugs
NER or dsDNA break repair XP = NER BRCA1/2 = dsDNA break repair
31
Platinum leaving groups
Cisplatin = chloride Carbo = cyclobutanedicarboxylate - needs esterase to chew off the leaving group Oxaliplatin = oxalate (this one has a large diaminocyclohexane backbone)
32
Platinums synergize with what drugs
5-FU and Gemcitabine Drugs that reduce purine and pyrimidine precursors
33
Mechanisms of resistance to L-spar
- ↑endogenous asparagine synthetase - Selects for cells that can upregulate synthesis of asparaginase (via hypomethylation of AspS gene) - Neutralizing antibodies - Defective induction of apoptosis
34
Drug interactions with L-spar
- Terminates action of methotrexate possibly due to inhibition of protein synthesis – cells refractory to MTX up to 10 days after L-asparaginase - ↑ toxicity of VCR
35
Zoledronate MOA
inhibits mevalonate pathway via inhibition of farnesyl pyrophosphate/diphosphate - R1 = responsible for binding to calcium (determines binding affinity) - R2 = responsible for potency
36
Toceranib targets
VEGFR2 PDGFRbeta KIT FLK2/FLT3 CSF1R
37
Sunitinib targets
RET CSF1R FLT3
38
Incidence of hypertension with Palladia
37% in Tjostheim study (> or =160mmHg)
39
Masitinib targets
Lyn KIT PDGFR
40
Imatinib targets
BCR-ABL - binds ATP pocket of ABL and RTKs such as KIT and PDGFRalpha
41
VEGF inhibitor
Bevacizumab
42
DNMT inhibitor
5-azacytidine
43
Mammary tumor types with prolonged survival
Carcinoma arising in benign mixed tumors Complex carcinoma Simple tubular carcinoma
44
Mammary tumor types with decreased survival
Tubulopapillary carcinoma Intraductal papillary carcinoma Malignant myoepthielioma Adenosquamous carcinoma Comedocarcinoma Solid carcinoma Anaplastic carcinoma Carcinosarcoma
45
What stimulates DC maturation
Antigen uptake
46
What stimulates CD8 T cell maturation from naive to effector
Antigen presentation from mature DC via MHC I with costimulation from CD80/86 binding CD28 on T cell
47
DC binding to immature CD4 cells needs what costimulators on DCs
CD80/86 on DC to bind CD28 on T cell ICAM on DC binds LFA on T cell
48
What ligands/receptor interactions between DCs and CD4 or CD8 T cells promote DC survival and increased cytokine production
CD4 - CD40L CD8 - 4-1BB
49
Th0 commits to Th1 path if stimulated in the presence of what cytokine transcription factor? Th1 produces what cytokines? Ultimate function of Th1 cells?
IL-12 TF = T-BET Th1 produce: IFN-gamma, TNF-alpha, IL-2 CTL function, tumor/virus/intracellular bacteria
50
Th0 commits to Th2 path if stimulated in the presence of what cytokine transcription factor? Th2 produces what cytokines? Ultimate function of Th4 cells?
IL-4 TF = GATA-3 Th2 produce: IL-4,5,6,10 B cell, allergies, asthma, IgE
51
Th0 commits to Th17 path if stimulated in the presence of what cytokine transcription factor? Th17 produces what cytokines? Ultimate function of Th17 cells?
TGF-beta, IL-6 TF = RORyt Th17 produce: IL-17 Autoimmunity, tissue inflammation
52
Th0 commits to Treg path if stimulated in the presence of what cytokine transcription factor? Treg produces what cytokines? Ultimate function of Treg cells?
TGF-beta, IL-10 TF = FOXP3 Treg produce: TGF-beta, IL-10 Suppression of immunity
53
Lymphangiosarc IHC
LYVE1+ PROX1+ *DIfferentiaties them from HSA
54
Myxoma IHC
Vimentin + CD18+ in 20-40% HSP25+ Cadherin 11+
55
Liposarc IHC
MDM2, CDK4
56
Leiomyosarc IHC
SMA + Desmin +
57
Rhabdo IHC
Vimentin+ Skeletal muscle actin + Myoglobin + Myogenin + MyoD +
58
PNST IHC
S-100+ Vimentin + GFAP + NGFR + NSE + Olig2 +
59
PWT IHC
SMA + (50%) Pan actin + Calponin + S-100, GFAP, NSE, Olig2 neg - differentiates them from PNST
60
IHC to differentiate PNST from fibrosarc
GLI1 and CLEC3B - pos in PNST and neg in FSA Sn 89% spec 87%
61
Synovial cell sarcoma px factors
Grade, mets at dx, stage
62
Met rate with synovial myxoma
0%
63
MLO met rate and recurrence rat e
55% met 50% recurrence w/sx
64
Turek paper sx + definitive RT + mito for agasaca
MST 956d, med event free ST 287d Late complications in half of dogs Acute colitis in 73%
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