Chemo Flashcards
1
Q
Amiloride is a___ and does what when combined doxorubicin chemotherapy? (Poon, JVIM 2019)
A
- Potassium sparing diuretic, inhibits sodium-hydrogen exchangers (NHEs that may contributed to tumor acidosis (Warburg effect) - Dox + amiloride synergistic, induce early and late apoptosis, upregulate p53 pathway = up Bax, down Bcl-xL and Akt phosphorylation
2
Q
Rate of clinical cardiotoxicity in dogs getting Dox (JVIM 2019, Hallman) Overall, high risk and non-high risk
A
Overall 4% High-risk 15.4% Non-high-risk 3%
3
Q
Factors associated with increased risk of clinical cardiotxicity in dogs getting dox (JVIM 2019, Hallman)
A
Higher cumulative dose, higher body weight, decreases in fractional shortening after 5 doses of DOX, development of VPCs
4
Q
Expression of which ABC transporters in B cell and T cell LSA are associated with chemoresistance? (Zandvliet Vet J 2015)
A
B cell: ABCB1 T cell: ABCG2
5
Q
What was the rate of neutropenia and thrombocytopenia from vinc in dogs that were either hetero or homozygous for MDR1 mutation compared to wt/wt dogs? (Mealey JVIM 2008)
A
mutants; 75% neutropenia, 62.5% thrombocytopenia wt/wt 11.5% neut, 4% thrombo too few dogs to compare hetero vs. homozygotes
6
Q
What doses of doxorubicin and vinc have been shown to cause increased tox in dogs heterozygous MDR1 mutations?
A
dox 22.5mg/m2 vinc 0.56mg/m2
7
Q
What type of mutation is present in dogs with ABCB1-1delta mutations? (Mealey JAVMA 2008)
A
4 base pair deletion that results in a frame shift that generates several premature stop codons
8
Q
What breeds have had their % of ABCB1 mutations updated since the Mealey JAVMA 2008 study?
A
English shepherd (0% in JAVMA, now 15%)
McNab (0% in JAVMA, now 30%)
Chinook (not reported in JAVMA, now 25%)
Mixd breed (11% in JAVMA, now 5%)
9
Q
What was the rate of PgP expression in cats with LSA? How did this affect survival or outcome? (Brenn VCO 2008)
A
14/63 (22%) for one Ab, 40/63 (63%) for other Ab
Neither predictive for remission duration or survival
10
Q
Which anatomic form of LSA in dogs was shown to express higher MDR1 compared to multicentric LSA? (Culmsee Res Vet Sci 2004)
A
GI LSA
11
Q
What is the MOA of methotrexate?
A
folate analog that inhibits dihydrofolate reductase –> depletes reduced folate pools needed for purine and thymidylate biosynthesis
12
Q
How does methotrexate enter the cell?
A
Via active transport via the reduced folate carrier
13
Q
Describe the oral bioavailablility of methotrexate
A
High at low does but becomes variable as doses increase –> high doses given IV
14
Q
Why can GI side effects be seen at lower doses of methotrexate that are not high enough to cause myelotox?
A
PK dominated by enterhepatic recycling
15
Q
What is the primary way methotrexate is excreted?
A
Primarlying intact drug through renal secretion and excretion
16
Q
What other anti-cancer drug can block toxicity and antitumor activity of methotrexate
A
L-spar
17
Q
T/F methotrexate does not distrubute into the CNS
A
False - modest distribution to CNS
18
Q
When is the peak toxicity for methotrexate
A
5-7d, returns to baseline w/in 14d
19
Q
How was intrathecal cytarabine and methotrexate tolerated in dogs? (Genoni VCO 2014)
A
Overall well, 1 dog had seizure during admin
20
Q
Why should caution be used in giving pregnant patients methotrexate?
A
Particular teratogenic (common amongst antimetabolites)
likely to develop anomalies of skull or distal limbs
spontaneous abortions if given during first trimester
21
Q
What is 5-FU?
A
halogenated analog of uracil
22
Q
How does 5-FU enter the cell?
A
Facilitated transport system (shared by adenine, uracil and hypoxanthine)
23
Q
What are the active forms of 5-FU
A
mono-, di- and triphosphate forms of fluorouridine and fluorodeoxyuridine
fluorodeoxyuridine monophosphate = FdUMP
24
Q
What are the primary MOA of 5-FU
A
Primary: FdUMP inhibits thymidylate synthetase –> preents thymidylate formation –> thymineless state = toxic to actively dividing cells
Other metabolites of 5-FU can be incorporated into RNA (FUTP)
Effects DNA synthesis/integrity
25
How is 5-FU excreted
Undergos extensive metabolism by dihydropyrimidine dehydrogenase (DPD) to dihydrofluorouracil and then to alpha-fluoro-beta-alanine, ammonia and CO2
90% metabolized; that + parent drug excreted primarily through biliary excretion
26
What are the primary tox of 5-FU to dogs?
Dose-dependent myelosuppression, GI tox and neurotox
\*\*ingestion of topical can be toxic and fatal\*\*
27
Why can't you give 5-FU to cats?
Severe CNS toxicity
28
What was the RR for dogs with gross disease carcinomas treated with concurrent 5-FU + carbo? CR was noted in 3 dogs with what cancer? (Menard VCO 2018) \*\*committee member\*\*
RR in gross disease = 43%
3 dogs with intestinal adenocarcinoma had CR
29
What AEs ocurred in dogs treated with concurrent 5-FU + carbo for carcinoma? (Menard VCO 2018) \*\*committee member\*\*
myelosuppression in 14/24 dogs (thrombo more common than myelo)
ataxic episode in 1 dog (not sure if otitis or 5-FU neurotox)
30
Why should you use caution in giving a pregnant patient 5-FU
highly teratogenic - deficits of nervous system, palate and skeleton
31
How does cytarabine enter the cell?
actively transported by nuceloside transporters (hENT1)
32
After entering the cell, cytarabine is phosphorylated sequentially by \_\_\_\_
CdR kinase (ara-c --\> ara-cmp)
dCMP kinase (aracmp --\>aracdp)
nucleoside diphosphate (NDP) kinase (ara-cdp --\> aractp)
33
What is the activated form of ara-c in the cell, and what is its moa?
ara-CTP
primary MOA: incorporated into DNA and terminates DNA chain elongation (varies with concentration and time)
other MOA: competitive inhibition of DNA polymerase alpha
34
Ara-C is (water/lipid)-soluble
water - distributes rapidly into the total body water
35
What % of plasma levels of ara-c are achieved in the CSF at steady state
60%
36
ara-c has its highest activity during what phase(s) of the cell cycle
s-phase
37
overexpression of ____ and ____ can antagonize ara-c mediate apoptosis
BCL2 and BCLX
38
How is ara-c eliminated
metabolized by cytidine deaminase in the liver, plasma and peripheral tissues
excreted in urine as ara-U
39
How does ara-c work synergistically with alkylators and platinums
ara-c inhibits DNA alkylation repair
40
What are the dlts of ara-c
usually myelosuppression, occasionally gi
41
What are 6-thioguanine and zebularine? (Flesner BMC 2014) \*\*committee\*\*
6-thioguanine = antimetabolite (purine analog)
zebularine cytidine anaolg with demethylating actvity + orally bioavailable
used in lymphoid malignancies
42
What is the MOA of 6-thioguanine and zebularine and what was found in vitro when lymphoid cells were treated with these? (Flesner BMC 2014) \*\*committee member\*\*
downregulateds DNA methyltransferase1 (DNMT1) through ubiquitin targeted degradation (5-azacytidine also works this way)
inv vitro each agent reduced DNMT1 and global DNA methylation + dose dependent decrease in cell survival (apoptosis primary mode of cell death)
43
What is the MOA of gemcitabine
inhibits DNA synthesis:
* potent inhibitor of ribonucleotide reductase (RNR) --\> depletion of deoxyribonucleotide pools --\> apoptosis
* weak inhibitor of DNA polymerase
* incorporation into DNA --\> strand termination
44
How does GEM enter the cell?
active transport via nucleoside transporters (HENT1)
45
What is the oral bioavailability of GEM
oral dosing = low systemic exposure likely because of extensive first pass metabolism in the liver
46
how is GEM eliminated
degraded via deamination by cytidine deaminase (GEM --\> dFdU) in liver, plasma and peripheral tissues
renal excretion
47
Dosing at what time in relation to RT causes the most prominent radiosensitizing effects of GEM
before RT by 24-60hrs
remember - horrible tox for dogs and cats treated with GEM + RT for head and neck carcinoma
48
What is the DLT of GEM
heme
49
What was the MTD of GEM and what was the DLT? (Marconato JVIM 2015)?
900mg/m2 30min IV bolus
neutropenia DLT (no non-heme DLT)
50
After what time period was GEM undetectable in the urine of dogs? (Marconato JVIM 2015)
24hrs
51
What are the adenosine analogs that are used in human oncology and generally what is their moa?
Fludarabine, pentostatin, cladribine, clofarabine
all inhibit ribonucleotide reductase and decrease pools of deoxynucleotides needed for DNA synthesis
most also can be incorporated into DNA as a false nucleotide
52
How does hydroxyurea enter the cell
passive diffusion
53
what is the MOA of hydroxyurea
inhibits RNR --\> decreases deoxyribonucleotide pools needed for DNA synthesis
54
hydroxyurea selectively kills _____ cells in ____ phase
rapidly proliferating; S phase
55
How is hydroxyurea distributed in the body?
distributes rapidly to well-perfused tissues, slowly enters CSF, readily enters breast milk
56
Which AEs from hydroxyurea are cats more susceptible to?
myelosuppressive effects and possibly methemoglobinemia at higher doses
57
What are the AEs related to hydroxyurea? What can happen in dogs after chronic treatment?
GI, myelosuppression (including anemia), rarely pulm fibrosis
dogs after chronic can develop onycholysis (painful detachment of the nail from the quick)
58
How is hydroxyurea eliminated
hepatic metabolism + urinary elimination of the parent compound
59
Pregnant cats treated at what dose of hydroxyurea can have what toxicity?
higher than recommended doses (100mg/kg/day) can have fetal tox
60
**What specific heme change has been found ain dogs treated with hydroxyurea? (Conrado Vet Clin Path 2017)**
**Mild anemia + macrocytosis w/o corresponding increase in polychromasia**
**MCV progressively increased with tx for MCT; highest value 100fL at 6mo, rapidly decreased after hydroxyurea d/c**
**take home: megaloblastic changes have been reported in multiple spp**
61
What is at the + end of the microtubule and what is its function?
GTP cap - stabalizes the microtubule and prevents its disassembly
62
What do microtubule associated protins (MAPs) do?
destabilize microtubules by promoting hydrolysis of GTP into GDP
63
What is the MOA of the vinca alkaloids?
* bind to a distinct site on tubulin and inhibit microtubule assembly --\> dirsuption of mitotic spindle apparatus --\> metaphase arrest and cytotoxicity
* also inhibits signaling at c-Jun-N-terminal kinase and cell surface TK --\> activate apoptotic pathway (malignant and non-malignant
* Inhibits BCL-2 and other anti-apoptotic proteins
64
How do the vincas enter the cell?
Passive diffusion (liophilic drugs)
65
How are the vincas excreted
extensive hepatic metabolism + biliary excreetion of parent drug and metabolites
10-20% of parent drug and metabolites excreted in urine
66
What are the primary mechanisms of drug resistance for the vincas?
innate or acquired MDR through ABC transporters (PgP, MDR-1, multidrug resistance protein (MRP1))
decreased expression of class III beta-tubulin --\> increases rate of microtubule assembly
67
Does VBL or VINC have a longer T1/2
Vinc - possibly reason for greater neurotoxicity
68
What are the differences in the toxicity profiles of Vinc and VBL
vinc less myelosuppressive than vbl, but vinc causes more peripheral neurotox and GI effects (ileus)
69
What's the plan for vinca extravasations
1. infuse 5-10ml saline around affected area (can add hyaluronidase 150U/1ml if you can get it)
2. Warm compress
3. Topical application of DMSO + flucinolone acetonide (synotic) + 10mg flunixin meglumine after each warm compress
70
What was outcome of platelet counts in dogs treated with vinc for LSA? (Campbell JSAP 2019
plt higher after tx + number of thrombocytopenic patients lower
okay to give vinc to dogs with lsa that are thrombocytopenic
71
What is the major cytochrome p450 in dogs that metabolizes vbl? (Achanta VCO 2016)
CYP3A12
72
What was the ORR and TTP for dogs treated with vinorelbine for various cancers (most pulmonary carcinoma or HS) (Wouda JAVMA 2015)
2% CR, 11% PR, 43% SD
TTP 103d
73
**What was the MTD and DLTs for cats treated with vinorelbine (Pierro JVIM 2013)**
**MTD 11.5mg/m2 weekly**
**DLTs - neutropenia, vomiting and nephrotoxicity**
**others: anemia, weight loss**
74
Compared to the antimetabolites, how teratogenic are the vinca alkaloids?
Less than antimetabolites, but can still cause spontaneous abortion, stillbirth and malformations
75
Are Border Collies that are ABCB1 WT more likely to develop vinc-associated myelosuppression (VAM) (Lind AJVR 2013)
according to this study, yes
3/5 BC developed VAM and no other dogs (21) developed VAM
No causative mutation found in this study, but 8 SNPs found in BC ABCB1
76
What was the effect of prophylactic maropitant (immediately after and for 4 days after) after treatment with either vinc or ctx? (Mason JSAP 2014)
No difference in AEs between those that had prophylactic maropitant and those that did not
overall AES: 69% of dogs getting vinc, 81% of dogs getting ctx
77
What was given to beagles treated with vinc that prevented reduced GI motility and resulted in fewer clinical GI AEs? (Tsukamoto JVIM 2011)
Mosapride citrate - gastroprokinetic agent that acts as a selective 5HT₄ agonist
78
**How long after administration was vinc detectable in the urine of dogs treated for LSA or MCT? (Knobloch JVIM 2010)**
**3 days after tx**
79
**How long after administration was vbl detectable in the urine of dogs treated for LSA or MCT? (Knobloch JVIM 2010)**
**7 days after treatment**
80
**How long after administration was ctx detectable in the urine of dogs treated for LSA or MCT? (Knobloch JVIM 2010)**
**immediately after cytoxan, median residue concentration = 398.2ug/l but non-detectable in subsequent days**
81
**How long after administration was doxo detectable in the urine of dogs treated for LSA or MCT? (Knobloch JVIM 2010)**
**21 days after treatment**
82
**How long after administration were VBL and CTX detectable in the serum of dogs treated for LSA or MCT? (Knobloch JVIM 2010)**
**VBL: detected in 1/81 samples 7d post treatment**
**CTX detected in 2 samples 1-2d after oral admin**
**conclusion: low risk of handling blood samples 1wk post-chemo**
83
**What is the MOA of paclitaxel (PTX) and docetaxel (DTX)**
stabilize microtubules aginst depolymerization
also, inhibit angiogenesis and **bcl-2**
84
What component of the microtubules do the taxanes bind with high affinity to
Beta-tubulin
85
What are the two most imortant ABC transporters involved in taxan resistance?
MDR1 (ABCB1) and MDR3 (ABCB4)
86
What is recommended when treating with paclitaxel?
Premeds - desamethasone, antihistamine H2 receptor antagonist (human recs)
87
What causes the hypersensitivity reactions seen with paclitaxel and docetaxel
The drug vehicles used - cremophor EL (paclitaxel), polysorbate 80 (docetaxel)
88
How are the taxanes excreted
rapid distribution, slow elimination
hepatic metabolism + biliary excretion primarily, 10% or less renally excreted
89
What are the DLTs for the taxanes
Diarrhea and neutropenia (remember, also causes hypersensitivity)
90
What was the rate of hypersensitivity when dogs were treated with IV or SQ excipient-free nanoparticulate formulation of paclitaxel? (Selting VCO 2018) \*\*committee member\*\*
No hypersensitivities, overall well tolerated but couldn't determine MTD because varied across dogs treated
91
What was the result of treating canine HSA cells with Paccal Vet (water-soluble micellar paclitaxel) (Reckelhoff VCO 2019)
Cell death in time and dose dependent manner
Significant increases in apoptosis; cell cycle arrest at G2/M phase
92
What were the AEs reported in 9 cats treated with paclitaxel (80mg/m2 IV q21d) for 1-2 doses? (Kim JFMS 2015)
AEs in 5/9 cats
Grade 3-4 thrombocytopenia
Grade 3 GI
Grade 3 hypersensitivity
93
What was the rate of hypersensitivity reactions, neutropenia and death due to sepsis in dogs treated with 165mg/m2 IV over 3-6hrs of paclitaxel? (Poirier JVIM 2004)
64% allergic reactions
24% grade 3-4 neutropenia
12% died from sepsis
94
**What is the MTD of docetaxel in cats? (JVIM 2011 Shiu)**
**2.25mg/kg**
95
**What were the AEs associated with 2.25mg/kg paclitaxel given to cats**
**DLT = neutropenia, vomiting, fever**
**hypersensitivity uncommon and mild**
96
**What were the recommended doses of dcetaxel and cyclosporine A for treatments in cats? (McEntee JVIM 2006)**
**MTD docetaxel 1.75mg/kg + 5mg/kg cyclosporine**
**able to achieve therapeutic plasma concentrations at lower doses when given with cyclosporine**
97
**What was the DLT and rate of hypersensitivity in dogs treated with 1.65mg/kg docetaxel + 5mg/kg cyclosporine A? (McEntee AJVR 2006)**
**No hypersensitivity**
**DLT = GI**
98
**What can you give less docetaxel to dogs when giving with cyclosporine and achieve similar plasma concentrations as with higher doses of docetaxel given by itself? (McEntee AJVR 2006)**
**Docetaxel = substrate for PgP and metabolized by CYP3A**
**Cyclosporine A modulates both PgP and CYP3A**
**Docetaxel or availability by itself ~20% but increases to almost 100% when given with cyclosporine**
99
What are epothilones and what cancer have they been used against in dogs? (Meier JVIM 2013)
Epothilone B (patupilone) = microtubule stabilizing agens
used in 20 dogs for LSA - MTD 2.76mg/m2, DLT = GI
100
**What was the MTD of IV cytoxan in cats? (Moore Vet J 2018)**
**480mg/m2**
101
**What was the DLT of ctx for cats at the MTD found in the Moore Vet J 2018 paper**
**neutropenia**
**30% grade 3-4 at 480mg/m2**
102
**What is the recommended dosage of ctx for cats treated with single agent cytoxan?**
**460mg/m2 q3wks**
103
**What was the highest inadvertently administered dose of cytoxan that resulted in a complete recovery in dogs? What were the AEs? Finlay JAAHA 2017**
**1750mg = 2,303mg/m2 over 21 days**
**severe SHC, severe nonregenerative pancytopenia, murmur (anemia?)**
104
What was CT able to incorporate into the BSA formula that the standard formula used does not? (Girens JVIM 2019) \*\*committee member\*\*
length
105
Was metronomic or pulse dose ctx more likely to cause SHC in dogs? What about GI or bone marrow? (Ekena VCO 2018)
SHC: metronomic
GI/bone marrow: pulse
106
**Elevated liver values were found in \_\_\_\_\_% of dogs treated with CCNU vs. \_\_\_\_\_% of dogs treated with CCNU + Denamarin (Skorupski JVIM 2011)**
**CCNU: 84%**
**CCNU + Denamarin: 68%**
107
**How did the degree of changes in liver values compare b/w dogs treated with CCNU vs. those treated with CCNU + Denamarain? (Skorupski JVIM 2011)**
**CCNU alone = greater increases in ALT, AST, SLP and bilirubin + more likely to have treatment delay or discontinue treatment**
108
**\_\_\_\_\_% of dogs treated with CCNU alone had grade 3-4 ALT elevation vs. \_\_\_\_% of dogs treated with CCNU + denamarin (Skorupski JVIM 2011)**
**CCNU alone: 60%**
**CCNU + Denamarin: 32%**
109
**CTX at low doses decreased what in dogs with STS? (Burton JVIM 2011)**
**Tregs and blood vessel density**
110
**CTX at 12.5mg/m2 caused a decrease in _____ in dogs with STS while CTX at 15mg/m2 caused a decrease in \_\_\_\_\_.**
**12.5mg/m2 = number of Tregs but not %Tregs or tumor microvessel density**
**15mg/m2 = both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days**
111
**What was the MTD for dogs treated with Idarubicin and what were the DLTs? (Vail JVIM 2012)**
**MTD in dogs \> 15kg = 22mg/m2**
**DLT = heme - neutropenia and thrombocytopenia**
112
**What is elsamitrucin (Fiocchi JVIM 2011)**
**Most potent topoisomerase II inhibitor available**
113
**What was the MTD of elsaitrucin in dogs? What were the DLT? (Fiocchi JVIM 2011)**
**0.08mg/kg) IV weekly**
**DLT = cardiac arrest (at 0.09mg/kg) severe diarrhea and anorexia**
**In people reportedly doesn't cause neutropenia or cardiotox**
114
**In dogs treated with pamidronate for bone pain, how many had increased BUN/Creat and how many had improved pain control if treated for OSA?**
**1/33 had increased BUN/creat**
**4/9 improved pain control for OSA**
115
**Reduction of ______ was found in the urine of dogs treated with pamidronate and _____ was shown with the primary tumor (Fan JVIM 2005)**
**N-telopeptide (**Urine N-telopeptide (NTx) excretion = mostsensitive and specific marker of bone resorption in humans with bone metastases
## Footnote
**enhanced bone mineral density of primary tumor**
116
**What was the MTD for pegylated TNF**α **in dogs? What was the DLT? (Thamm Clin Cancer Res 2010)**
**MTD 26.7ug/kg**
**DLT = vascular leak and coagulopathy/hypotension**
**Most common AEs = fever, diarrhea and vomiting**
117
**What limits the clinical utility of TNF**α? **(Thamm Clin Cancer Res 2010)**
**Short T1/2**
**pegylated TNF**α **has increased cirulating T1/2, dcreased immunogenicity --\> decreased toxicity**
**Increased intratumor drug concentration**
118
What was the MTD and DLT for a combination protocol of carbo/TOC? (Wouda VCO 2018) \*\*committee paper\*\*
200 mg m-2 IV every 21 days and approximately 2.75 mg kg-1 PO EOD, respectively.
The dose-limiting toxicity was neutropenia.
119
What were the primary toxicities of hylauronan-cisplatin nanoconjugate (HA-Pt) in dogs? (Cai AJVR 2016) \*\*committee paper\*\*
37% myelosuppression 12.5% cardiotox, elevated ALT
No dogs had nephrotox
conclusion: effective in tumor bearing dogs, but high AE profile
120
**What is satraplatin? (Selting JVIM 2011)**
**Oral platinum drug**
121
**What is the MTD of satraplatin in dogs, what was the DLT? (Selting JVIM 2011)**
**MTD: 35mg/m2/day for 5d every 3-4 weeks**
**Myelosuppression = DLT**
**thrombocytopenia at d14, neutropenia at d19**
122
What was the effect of Palladia on thyroid function in dogs? (Harper VCO 2019)
No dogs had low TT4, but significantly higher TSH in TOC dogs at 6wks vs. baseline
123
What was the MTD for doxorubicin + TOC in dogs? What was the DLT? (Pellin VCO 2017) \*\*Committee member\*\*
MTD: 25mg/m2 doxorubicin q21d + 2.75mg/kg palladia EOD
DLT = neutropenia
124
**What was the overall biologic response rate in cats treated with palladia for advanced neoplasia? what was the median duration of the response? (Harper JFMS 2017)**
**RR 57.1%**
**median duration: 90d**
**\*\*no SCC cats had a response\*\***
125
**What AEs were reported in cats with advanced neoplasia treated with TOC? (Harper JFMS 2017)**
**10/14 had AEs, most mild myelosuppression or GI**
**2 cats developed severe hepatotoxicity**
126
**What heme changes were found in dogs treated with a combination of TOC + metronomic cytoxan? (Mitchell JVIM 2012)**
**Toc sig decreased # and % of T regs in blood**
**TOC + CTX had increased IFN gamma, and decreases in Tregs**
127
**What was the result of combining Masitinib increased the sensitivity of what cancer cells to vinblastine? What about Gem?**
**Increased sensitivity of HS to VBL**
**Increased sensitivity of OSA and Mammary to Gem**
128
**What was the % clincal benefit in dogs with AGASACA treated with Palladia (London VCO 2011)**
**28/32 (87.5%)**
**8PR, 20SD**
129
**What was the CB of Palladia for dogs with OSA? (London VCO 211)**
**11/23 = 48%**
**1PR, 10SD**
130
**What was the CB for dogs with thyroid carcinoma treated with Palladia? (London VCO 2011)**
**12/15 = 80%**
**4PR and 8SD**
131
**What was the CB for dogs with head/neck cancer (SCC) treated with palladia? (London VCO 2011)**
**7/8 = 87.5%**
**1 CR, 5PR, 1 SD**
132
**What was the CB for dogs with nasal carcinoma treated with Palladia? (London VCO 2011)**
**5/7 = 71%**
**1 CR, 4 SD**
133
**What was the overal clinical benefit for Palladia in solid tumors in dogs and what was the dosing used? (London 2011 VCO)**
**clinical benefit in 74% of dogs**
**median 2.8mg/kg M, W, F**
134
**What was the MTD for CCNU + TOC? What was the DLT? (Pan VCO 2014)**
**Toc: 2.75mg/kg EOD + 50mg/m2 CCNU q3wk**
**DLT = neutropenia**
135
**Wha3t was the ORR and biologic response to CCNU + TOC (Pan VCO 2014)**
**ORR 38.4%**
**Biologic response 53.8%**
136
**What was the MTD of vbl + toc for dogs with MTC? (Robat VCO 2011)**
**TOC: 3.25mg/kg EOD + VBL 1.6mg/m2 q2wks**
**\>50% reduction in dose intensity for vbl**
137
**What was the ORR for dogs with MCT treated with VBL + TOC? (Robat VCO 2011)**
**71% response rate (+ enhanced myelosuppression)**
138
**What 2 doses of masitinib were compared in cats and what were the AEs noted? (Daly JVIM 2011)**
**50mg EOD or 50mg q24hrs**
**2 cats developed clinically relevant proteinuria (10%) - both in daily dosing**
**Neutropenia in 15% of cats (mix of treatment groups)**
**some GI and increased creat**
139
What does eBAT target? (Oh clin pharm 2018) \*\*committee paper\*\*
targets EGFR on cancer cells and urokinase plasminogen activator receptor on cancer cells + associated vasculature
140
**What was the rate of proteinuria in dogs with cancer?What were the rates of the three levels assessed? How many azotemic or hypertensive? (Prudic JSAP 2018)**
**Overall 51% proteinuric**
**15% overtly**
**36.7% borderline**
**48.3% non-proteinuric**
**none azotemic**
**30% hypertensive**
141
What was the ST for dogs with HSA treated with splenectomy + dox followed by e-bat in the phase 1/2 study? (Borgatti mol canc ther 2017)
\*\*committee member\*\*
Improved 6mo survival from \<40% to \>70%
6 long term survivors
142
What are the three forms of asparaginase that are available?
E.coli
pegylated e. coli asparaginase
erwinia crysanthemi asparaginase
143
What are the advantages and disadvantages of pegylated e. coli asparaginase
nonimmunogenic in 70% of patients that reacted to e. coli asparaginase, but retains only 50% of activity
144
What is the MOA of L-spar
enzyme hyrolyzes L-asparagine and displaces NH3 to form L-aspartate --\> depletes L-asparagine and impairs protein synthesis --\> apoptosis in lymphocytes
145
What can irreversibly inhibit the reaction of asparaginase --\> aspartate?
5-diazo-4-oxo-l-norvaline
146
What are the main resistance mechanisms to L-spar
Upregulation of asparagine synthase
downregulation of apoptotic pathways
production of neutralizing Abs (silent hypersensitivity) - anti-lspar abs in 30% after 1st use and 60% after 2nd use
147
What is the rate of anyphlaxis to l-spar in dogs and cats
dogs: 4.2%
cats: 0%
148
Why should you not use l-spar near the time of surgery?
L-spar decreases protein synthesis and can cause hypoalbuminemia
149
What may drive panc secondary to L-spar?
impaired protein metabolism --\> hypertriglyceridemia
150
Which clotting factors are particularly affected by l-spar
decreased vitamin K dependent (2, 7, 9, 10) and decreased anticoagulant factor production (AT III)
151
What are the known drug interactions of l-spar
blocks activity of methotrexate
increases sensitivity to vinc
152
What is the ORR to L-spar in cats? (LeBlanc 2007)
30%
15% CR, 15% PR
153
Was there a difference in the AEs or ORR between compounded and commercially available L-spar? (Thiman 2016)
Nope.
154
Why must small molecule inhibitors be dosed more frequently than monoclonal ab
both require constant pathway inhibition to inhibit the tumorigenic effects - shorter t1/2 means need more frequent dosing (like small molecule inhibitors) vs. longer t1/2 can be dose more intermittently (mAbs)
155
What are the two main tyrosine kinase treatment strategies in humans?
1. mAbs - block ligand binding, induce receptor endocytosis and destrcution or induce immune mediate cellular lysis
2. RTKIs - bind to the ATP binding pocket and prevent activation
156
What does toceranib target?
it is a split kinase - binds multiple things
* Kit (SCFR)
* CSF-1 (macrophage colony stimulating factor)
* VEGFR2
* PDGFR
* FGFR
* Flt-3
* Flk-2
157
What c-kit mutations are most commonly found in canine MCT? What about Cats?
dog: internal tandem repeats at the juxtamembrane region (exon 11\>12) and less commonly extracellularly (exon 8\>exon 9)
cats: extracellularly exon 8
158
what are the ckit mutations found in GISTs
deletions in the juxtamembrane region
159
What is the lowest evaluated dose of TOC that was found to be efficacious? (Bernabe BMC 2013)
2.4mg/kg PO EOD
160
What is the metabolism of TOC?
Long T1/2 - 31hrs
primarily biliary with 92% excreted in feces
enterohepatic circulation
161
What is the rate of hypertension secondary to TOC? (Tjostheim JVIM 2016)
37%
162
What is the rate of elevated LEs with TOC + pred? What resolved this? (Carlsten JVIM 2012)
80%; resolved w/ denamarin
163
What does Imatinib target?
c-kit, BCR-ABL, Src, PDGFR
164
What is the MOA of rapamycin
binds to FKBP-12 or FK506 and inhibits mTOR activity
Can trigger p53 independent apoptosis
decreases expression of cyclin d1
165
Rapamycin may inhibit _____ with prolonged use but _____ alteration was not detected in dogs
AKT
166
What is a unique AE associated with IM injection of rapamycin?
sterile abscesses
167
What are the rapamycin analogs and what do they block specifically?
temsirolimus/everolimus
block TORC1
168
What are the most popular viruses used in gene therapy?
adenoviruses
169
\_\_\_\_\_ deleted adenoviruses only replicate in cells deficient in \_\_\_\_\_
E1b; p53
170
\_\_\_\_\_\_ is a mAb targeting VEGF
Bevicizumab
171
NSAIDs that target COX2 have been shown to reduce ____ and ____ in TCC
FGF and VEGF
172
What is the MOA of thalidomide?
binds E3 ligase cereblon --\> ubiquitination and proteasomal degradation of proteins including Ikaros and Aiolos
inhibits FNF-alpha production and redcued VEGF
stimulates T cell response against tumor cells and NK cells
173
What was the average metronomic CCNU dose and what differences in AEs were noted between MTD CNNU and metronomic CCNU? (Tripp 2011)
2.84mg/m2
higher rates of azotemia for metronomic (10%, progressive in 1%)
lower rates of hepatotoxicity in metronomic (14%) than MTD (30%)
174
What are examples of HDAC inhibitors?
vorinostat, romidepsin, valproic acid
175
What are bortezomib and carfilzomib? How do they work?
proteasome inhibitors
targets and inhibits the 26s proteasome (which destroys damaged or misfolded proteins) --\> halts protein synthesis and triggers autophagy
176
Traztuzimab binds \_\_\_\_\_
HER2
177
What are the bifunctional calssical alkylators?
nitrosoureas, nitrogen mustards
178
What are the monofunctional alkylators
procarb, dacarbazine, TMZ
179
CTX is oxidized by \_\_\_\_
cytochrome p450
180
What toxicity can be causes at the doses of CTX used for bone marrow transplant?
cardiac toxicity
181
How is melphalan metabolized and excreted?
no active metabolism, all spontaneous decomp (hydrolysis)
30% excreted unchanged in the urine
182
What is the unique mechanism of drug resistance to melphalan?
decreased uptake due to downregulation of leucine transporters
183
What chemo drug has the highest rate of secondary hematopoietic malignancy?
melphalan
184
CCNU is lipid or water soluble?
Lipid - enters cell by passive diffusion
185
How is CCNU excreted?
urine
186
What drug interactions are known for CCNU?
drugs that upregulate cytochrome p450 increase rate of clearance and decrease efficacy of CCNU - important for pheno (CNS LSA)
187
