Chemo/Targeted Flashcards
1
Q
What effects does mCTX have on STS?
A
decreased blood vessel density, depleted Tregs (immunomodulatory)
2
Q
What kind of T cells are Tregs?
A
CD4+
3
Q
What is rosiglitazone?
A
peroxisome proliferator-activated receptor gamma (PPARγ) agonist and antidiabetic agent in humans
4
Q
What supportive care medication decreases permeability of the BBB? (Chabner)
A
corticosteroids
5
Q
What are two ways antifolates inhibit DNA biosynthesis?
A
- partial depletion of reduced-folate substrates
2. direct inhibition of folate-dependent enzymes
6
Q
What does methotrexate inhibit?
A
dihydrofolate reductase (DHFR) - results in depletion of reduced folates
7
Q
How is methotrexate transported into the cell?
A
reduced folate carrier system
8
Q
What are 5 mechanisms of resistance to methotrexate?
A
- decreased transport into cell
- increased efflux by MDR1, MRP1, 2, 3, BCRP
- decreased intracellular polyglutamation
- decreased binding to DHFR (due to mutation)
- gene amplification of DHFR
- changes in level/affinity for thymidine synthase
9
Q
How does L-spar affect methotrexate?
A
blocks activity (through AA deprivation)
10
Q
How do NSAIDs affect methotrexate?
A
decrease renal clearance, increase toxicity
11
Q
How does methotrexate affect 5-FU and Cytosar?
A
increases activity
12
Q
How is MTX metabolized?
A
- converted to poly glutamates within cells (by follypolyglutamyl synthetase); polyglutamated MTX retained intracellularly
- metabolized in liver
13
Q
How is MTX excreted?
A
excreted as intact drug in urine - dose reduce with CKD!!
14
Q
What is leucovorin?
A
source of reduced folate - used 24-36h after high dose MTX; decreases/prevents toxicity via competition
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
16
Q
Is MTX cell-cycle specific?
A
Yes - S-phase
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
18
Q
How is 5-FU transported into the cell?
A
shares facilitated transport with uracil, adenine, hypoxanthine
19
Q
What are 5 mechanisms of resistance to 5-FU?
A
- decreased uptake (mutations in nucleoside transporters)
- increased efflux
- decreased activation
- increased activation by DPD
- mutations of thymidylate synthase
20
Q
How do cimetidine and IFNalpha affect 5-FU?
A
decreased clearance
21
Q
How does 5-FU interact with radiation?
A
radio sensitization through decrease in dTTP pools – inhibits DNA repair
22
Q
5-FU inhibits metabolism of which two drugs?
A
warfarin, phenytoin
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)
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
25
What important 5-FU enzyme has been evaluated in cats? What were the findings? (Saba 2013)
DPD
23% had value associated with decreased DPD activity (based on human studies)
Measured U:UH2
26
How is 5-FU eliminated?
90% by catabolism/anabolism
| <10% excreted in urine and lungs (urea, CO2)
27
How does toxicity differ between CRI and bolus of 5-FU?
```
CRI = mucositis
Bolus = myelosuppression
```
28
What are the toxic and fatal doses of 5-FU in dogs?
>20 mg/kg = neurotoxicity
| >43 mg/kg = fatal
29
What toxicities does capecitabine cause in dogs?
corneal and neurotoxicity
30
What does bevacizumab target?
VEGF-A ligand
| humanized mAb
31
What does trastuzumab target?
HER-2
| humanized mAb
32
What is cytosar an analog of?
deoxycytidine (precursor of dCTP)
33
What is the rate-limiting step of cytosar metabolism?
Deoxycytidine kinase enzyme converts Ara-C to Ara-CMP
34
What is the active form/metabolite of cytosar?
Ara-CTP
35
What is the MOA of cytosar?
Inhibition of DNA polymerase-alpha
| Ara-C becomes incorporated into DNA to cause DNA chain termination and induction of apoptosis
36
How is cytosar transported into the cell?
carrier-mediated process via nucleoside transporters
37
What are mechanisms of resistance to cytosar?
1. decreased activation by deoxycytidine kinase
2. increased activation by deaminases (produces inactive metabolite Ara-U)
3. decreased drug uptake (mutation in nucleoside transporters)
38
Is cytosar cell cycle specific?
Yes (S-phase)
39
What PK parameter determines efficacy of cytosar?
duration of exposure (correlates with cell kill)
| this is also the case for MTX, vincas, taxanes
40
What is the role of cytosar in canine stage V LSA? (Marconato VCO 2008)
dogs with bone marrow involvement treated with CHOPL and Cytosar - MST 243d (vs. 72.5 with CHOPL alone); dogs received both EPO and Neupogen
41
What is the metabolism for gemicitabine? (apparently less important than cytosar and Cytoxan)
dFdc is phosphorylated by deoxycytidine kinase to dFdCMP --> dFdCDP --> dFdCTP
42
Where is gemcitabine inactivated?
Inactivated by deaminases in the LIVER (reduce dose for liver dysfunction)
43
What is the MOA of gemcitabine? (two things)
- 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)
44
How is gemcitabie transported into the cell?
carrier-mediated transport via nucleoside transporters
45
Name 4 mechanisms of resistance to gemcitabine.
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)
46
What is the mechanism of radiosensitization with gemcitabine?
inhibition of ribonucleotide reductase (results in decreased deoxyribonucleotide pools necessary for DNA synthesis)
47
What was the RR with gem/carbo for carcinomas? % GI toxicity? (Dominguez 2009)
RR 13% (prostatic carcinoma had a CR, GI ACA and tongue SCC had PR)
73% GI toxicity (usually mild)
48
What responses were seen with gem/carbo for feline carcinomas? What was toxicity? (Martinez-Ruzafa 2009)
1 CR, 1 PR
| 33.3% neutropenia, 16.7% thrombocytopenia, 16.7% GI dox (similar to any chemo protocol)
49
What were the results of a phase 1 study with gemcitabine in dogs? MTD, DLT, detectable in urine, tumor responses? (Marconato JVIM 2015)
MTD 900 mg/m2 (weekly)
DLT neutropenia
Tumor responses in TCC, mammary, primary lung
50
What is the MOA of 5-azacytidine and decitabine?
Inhibit DNA methyltransferase to inhibit DNA methylation and promote expression of suppressed genes
Also incorporated into DNA +/- RNA
51
What is 6-MP? What is it a structural analog of?
Guanine analog
| Hypoxanthine
52
How is 6-MP metabolized?
Activated intracellularly by HGPRT (hypoxanthine guanine phosphoribosyl transferase) to TIMP -- metabolized to thioguanine nucleotides which are the active products
53
How is 6-MP catabolized?
By xanthine oxidase and TPMT (thiopurine methyltransferase)
54
Why is genetic screening for TPMT (thiopurine methyltransferase) important in humans?
low activity can result in decreased drug metabolism and increased toxicity
55
What is the MOA of 6-MP?
incorporation of thioguanine metabolites into DNA - causes miscoding, results in apoptosis via MMR
(secondary MOA - also inhibits purine synthesis, incorporation into RNA)
56
What drug interaction is seen with 6-MP and allopurinol?
concurrent use causes inhibition of XO which increases 6-MP activity
57
What is the metabolism of 6-TG (thioguanine)?
activated to TGMP (6-thioguanylic acid) by HGPRT (hypoxanthine guanine phosphoribosyl transferase)
58
How is 6-TG catabolized?
By TPMT (NOT XO)
59
What is the MOA of 6-TG?
incorporates TGMP into DNA, triggers apoptotic with MMR
60
What were the results of 6-TG and zebularine with canine malignant lymphoid cells? (Flesner BMC Vet Res 2014)
- Down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells
- dose-dependent decrease in cell survival was also observed (apoptosis)
61
What is azathioprine's metabolism and MOA similar to?
6-MP
62
What is zebularine?
nucleoside analog of cytidine, also inhibits DNA methylation
63
What are the uses of allopurinol?
prevention of hyperuricemia and uric acid nephropathy
| NOT NEEDED in dogs, hyperuricemia not a problem - different pathway
64
What electrolyte abnormalities are seen in TLS?
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
65
What is the MOA of allopurinol?
inhibition of xanthine oxidase (to inhibit conversion of xanthine and hypoxanthine to uric acid)
66
Name two important drug interactions with allopurinol.
Increases half-life of 6-mercaptopurine and azathioprine
67
How does rasburicase treat TLS?
recombinant urate oxidase (aka uricase - most mammals have this enzyme but humans don't) that converts uric acid to allantoin
68
Why doesn't uric acid accumulation occur in dogs with TLS?
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.
69
What is the main MOA of hydroxyurea?
inhibition of ribonucleotide reductase (rate-limiting enzyme in de novo synthesis of deoxyribonucleotide triphosphate)
70
How does hydroxyurea enter cells?
passive diffusion
71
Is hydroxyurea cell-cycle specific?
Yes, S-phase
72
How is hydroxyurea excreted?
renal excretion - decrease dose with renal dysfunction
73
What is the main MOR to hydroxyurea?
increased ribonucleotide reductase activity
74
How does hydroxyurea affect the activity of anti-metabolites?
increases their activity by reducing competitive pools of physiologic triphosphates
75
Which drugs should be avoided or dose reduced in patients with azotemia? (5)
```
cisplatin
etoposide
carboplatin
bleomycin
methotrexate
```
76
Which drugs should be avoided or dose reduced in patients with hepatic dysfunction/hyperbilirubinemia? (8)
```
paclitaxel
etoposide
vincristine
vinblastine
vinorelbine
docetaxel
mitoxantrone
doxorubicin
```
77
Which cancers have shown a PR to piroxicam as single agent? (Knapp 1992, also Eichstadt 2016)
TCC, TVT, SCC, mammary carcinoma
78
What cell cycle phase transition is blocked by gemcitabine?
G1 to S phase
79
What is the active form of gemcitabine (once it gets into cell)?
dFdCTP
80
What enzyme regulates the rate limiting step of gemcitabine metabolism?
deoxycytidine kinase (dCK)
81
What rate of gemcitabine administration is recommended in cats to achieve target plasma concentration (TPC)? (Garnett, Rodriguez 2016)
Fixed dose-rate between 2.5-5 mg/m2 per minute.
82
What two things does folate depletion interfere with?
nucleotide synthesis and DNA methylation
83
What happens when dTMP synthesis is inhibited in conditions of low folate?
Uracil is incorporated in to the DNA instead
| Both uracil disincorporation and DNA strand breaks are observed in folate-deficient humans
84
Why does cyclophosphamide spare platelets?
May be due to increased aldehyde dehydrogenase in stem cells - inactivates CTX
85
What is the active form of CTX?
phosphoramide mustard
86
What drug type is particularly teratogenic?
antimetabolites
87
What are the targets of masitinib?
KIT, PDGFR, Lyn
88
What is bevacizumab?
Humanized IgG1 mAb against VEGF
| treats colorectal cancer
89
What is cetuximab?
chimeric IgG1 mAb against EGFR
| treats colorectal cancer
90
What is the difference in MOA between low and high doses of vinca alkaloids?
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
91
How are vincas transported into the cell?
passive diffusion
92
What is the most important determinant of cytotoxicity of the vinca alkaloids?
duration of exposure above a critical threshold
93
Two main mechanisms of resistance to vincas and taxanes?
- increased drug efflux
| - alterations in tubules that confer hyperstability
94
How do you dose vinc in patient with hepatic dysfunction?
At UMN:
If t.bili >2.0 – Decrease by 75%
If t.bili 0.6 – 1.9 – Decrease by 50%
95
What are 3 cytochrome p450 inducers? How do they affect vincas?
phenobarbital, phenytoin, rifampin, steroids
| decreased VCR efficacy because increased metabolism
96
What are 3 cytochrome p450 inhibitors and how do they affect vincas?
erythromycin, ketoconazole, cimetidine
| increase VCR toxicity because decreased metabolism
97
What are DLTs of vincas?
VCR: peripheral neuropathy
| VBL, VRL, VFL, VDS: neutropenia
98
What endocrine toxicity is possible with vincas?
SIADH (hyponatremia, seizures)
| also caused by CTX, cisplatin, thiazides, morphine, pulmonary/CNS infections
99
What is the proposed MOA for vinc's ability to increase circulating PLT?
causes endoreduplication (replication of genome in absence of cell division) of megakaryocytes
100
MOA of taxanes? Where do they bind?
```
inhibit depolymerization (disassembly) of tubulin
bind interior of microtubules
```
101
Would you expect a tumor resistant to vinc and DOX to respond to paclitaxel?
No - MDR1 resistance
102
How does paclitaxel interact with DOX? Cisplatin?
DOX - reduced clearance, increased cardiotox
| CIS - given before paclitaxel reduces clearance of paclitaxel
103
What is the incidence of hypersensitivity in dogs treated with IV paclitaxel? How does Paccal Vet avoid this?
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)
104
What is the MTD of oral docetaxel in dogs and cats?
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
105
MOA of epothilone B? MTD and DLT of epothilone B in dogs?
inhibits tubulin depolymerization
MTD 2.76 mg/m2 IV weekly
DLT was GI
106
Is there cross-resistance in taxanes?
No
| not affected by over expression of MDR1
107
What drugs are nitrogen mustards? (alkylating agents)
mustargen, melphalan, chlorambucil, CTX, ifosfamide, bendamustine
108
What drugs are nitrosureas? (alkylating agents)
CCNU, BCNU, streptozotocin
109
Which agents are the most carcinogenic?
mustargen and methylating agents
110
What is a monofunctional alkylating agent? Bifunctional?
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
Which drugs are monofunctional alkylating agents?
procarbazine, DTIC, CCNU
112
Which drugs are bifunctional alkylating agents?
nitrogen mustards, BCNU, aziridines, alkyl sulfates (busulfan)
113
What is present in tumor cells that are resistant to CTX?
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
What are the toxicities of CTX in humans? (4)
myelosuppression (PLT sparing), SHC, hemorrhagic myocarditis, SIADH
115
What drug is recommended for mustargen extravasation?
sodium thiosulfate
116
What is the active metabolite of ifosfamide? What are toxicities of ifosfamide in humans? (4)
isophosphoramide mustard
mild myelosuppression, SHC, neurotoxicity (chloroacetylaldehyde metabolite), nephrotoxic at high doses (Fanconi-like syndrome)
117
Name 3 drugs that are associated with pulmonary fibrosis? (BBB)
Busulfan, BCNU, bleomycin
118
Regarding PK parameters - efficacy of alkylating agents is related to what?
AUC
119
T/F: dexamethasone is an effective chemoprotectant agent in dogs receiving CCNU.
False - Intile VCO 2009, did not prevent myelosuppression
120
What are risk factors for developing SHC in canine LSA patients?
increased cumulative dose (odds increase by 2.21 per 750 mg/m2), short induction protocol decreased risk
121
Preferred alkylating sites of busulfan, mustargen, melphalan?
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
Preferred alkylating sites of nitrosureas, procarbazine, dacarbazine?
Nitrosurea - O-6 position of guanine
Procarbazine - O-6 position of guanine
Dacarbazine - O-6 position of guanine
123
T/F: Methylating agents are prodrugs.
True
124
Are methylating agents mono or bifunctional?
monofunctional
125
What is the MOA of methylating agents?
methylation of nucleic acids (forms O6-methylguanine)
| inhibits DNA, RNA, protein synthesis
126
What are the MOR to methylating agents?
increased MGMT-mediated repair of O6-methylguanine
| MMR deficiency
127
What toxicities were seen with tumor-bearing cats treated with DOX + TMZ?
Gagnon JFMS 2012
grade 3/4 hematologic toxicity, GI toxicity
pleural/pericardial effusions seen with higher cumulative doses of TMZ
128
Why were cats in the DOX/TMZ study euthanized? (Gagnon JFMS 2012)
severe/prolonged myelosuppression with fever
pleural effusion
pericardial effusion
(effusions were seen in cats with higher cumulative doses of TMZ)
129
When in the cell cycle are topoII inhibitors most active?
Late S/G2 - but not really cell cycle dependent
130
What are 3 MOR against topoII inhibitors?
1. efflux due to MDR1, MRP1, BCRP
2. GSH-mediated drug inactivation
3. decreased topoII levels
131
What is the acute DLT of topoII inhibitors in people?
myelosuppression
132
W/hat carrier can cause patients receiving etoposide to have allergic reactions? Are topoII inhibitors carcinogenic?
Polysorbate 80
| Yes - develop AML 24-30 months after tx
133
Is oral etoposide bioavailable in dogs?
No - Flory 2008
| HS rxn to IV etoposide seen in 50% d/t polysorbate 80
134
What is elsamitrucin and the results of a phase I trial?
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
From which two bacteria is L-spar derived?
E-coli and Erwinia
136
What is MOA of L-spar?
converts asparagine to aspartic acid and ammonia
137
What are 3 MOR to L-spar?
1. upregulation of asparagine synthetase
2. formulation of neutralizing AB
3. defective induction of apoptosis
138
Name 5 possible toxicities secondary to L-spar?
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
What effect does L-spar had on vinc and MTX?
decreased hepatic clearance of vinc
| blocks activity of MTX
140
Where is ifosfamide activated?
Requires metabolic activation by microsomal mixed function oxidases in liver (not in the cell)
141
What is the role of the ubiquitin-proteasome pathway? What are the two major components?
degradation of intracellular proteins
| 1 - ubiquinating enzyme complex, 2 - proteazome
142
What is the MOA of bortezomib?
inhibits proteasome (boronia acid on bortezomib binds threonine on the proteasome to prevent protein degradation)
143
In which two human cancers is bortezomib used?
MM and mantle cell LSA
144
What are the 3 major effects of proteasome inhibition?
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
How do HDACi affect histone?
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
What kind of drug is valproic acid?
HDACi
| significant growth inhibition and apoptosis in combo with DOX (Wittenburg CCP 2011)
147
What is the diffusion limit of O2? What is the critical step in initiation of the angiogenic switch?
100uM
| Activation of Hif-1
148
What are the main ligand and receptor for angiogenesis?
VEGF-A
| VEGFR2
149
What is the MOA of bevacizumab? What veterinary cancer has this been studied in?
targets VEGF ligand
| OSA - inhibited tumor growth in mice
150
What are the targets of sorafenib?
VEGFR, PDGFR, Flt3, KIT, RET, Raf kinase
151
What are the targets of sunitinib?
VEGFR, PDGFR, Flt3, KIT, RET, CSF-1R
152
How are sorafenib and sunitinib metabolized?
All TKIs are CYP3A4 (cytochrome p450) metabolized
153
What are the targets of toceranib?
VEGFR, PDGFR, Flt3, KIT, CSF-1R
154
What are the targets of masitinib?
PDGFR, KIT, Lyn
155
What are the targets of imatinib? What is its MOA?
BCR-ABL, PDGFR, KIT
| Targets ATP binding site of the TK and fixes the enzyme in inactive conformation
156
In which human cancers is imatinib used?
CML, GIST
157
What were results of a phase I of imatinib in cats? Dose?
10 mg/kg q24h recommended
well-tolerated
tumor stabilization in ISS
158
What were the results of imatinib in canine MCT?
48% RR, 10 mg/kg q24h, minimal toxicity
| hepatotoxicity previously seen at 100 mg/kg
159
What mutation in HER2 is seen in breast cancer?
amplification - associated with more aggressive phenotype
160
What is the MOA of trastuzumab?
binds to extracellular domain of HER2
161
What are the MOR to trastuzumab?
mutation in extracellular domain of HER2
activation of downstream signals
activation of alternative GF pathways (growth factor)
162
What is the MOA of lapitinib?
TKI that targets HER2 and EGFR
163
What is the MOA of thalidomide?
direct pro-apoptotic effect, inhibits protective effect of BM stroma (for MM specifically), inhibit cytokine production, anti-angiogenesis, immunomodulation (stimulates NK/T-cells)
164
For which human cancer is thalidomide used?
MM
165
In which veterinary cancers has thalidomide been studied?
feline OSCC (combo w/piroxicam, bleo, RT, surgery); Canine OSA xenotransplant; canine lung tumors
166
What is the MOA of tamoxifen? Where is it anti- and pro-estrogenic?
selective estrogen receptor modulator
| anti-estrogenic = breast; pro-estrogenic = bone, CV tissue, uterus, liver
167
What side effects of tamoxifen were seen in dogs?
vulvar enlargement/discharge, attractiveness to males, nesting behavior, pyometra in intact females (Morris 1993)
168
Name the steroidal hormonal treatment.
Fulvestrant - pure anti-estrogen
169
How do steroidal and non-steroidal aromatase inhibitors work? Give examples of each.
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
How do LHRH/GnRH agonists work against breast cancer? What is the acute flare up?
inhibit gonadotropin secretion to inhibit estrogen production
initial increase in LH, FSH, and estrogen may cause acute exacerbation of dz
171
What drugs are used in chemoprevention of prostate cancer? What is their MOA?
finasteride, dutasteride
| inhibit 5a-reductase (converts testosterone to DHT which is most potent form of androgen)
172
What was the max tolerated target AUC for a single dose of carboplatin in cats (using GFR)?
2.75 min•mg•mL−1
173
What is the equation for calculating dose of carboplatin in cats based on GFR? (Bailey 2004)
Dose = AUC x 2.60 x GFR x BW(kg)
174
What is the difference between topoI and topoII?
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
What is the MOA of topoI inhibitors?
stabilize cleaved complex and prevent re-ligation
176
During which cell phase are topoI inhibitors most active?
S-phase (but are not totally cell cycle specific)
177
What is the most active metabolite of irinotecan? How is this metabolite catabolized?
SN-38
| catabolized by UDP-glucoronyl transferase - this enzyme is highly polymorphic in the human population
178
What are the major toxicities to irinotecan?
- DLT - delayed diarrhea and neutropenia
| - cholinergic symptoms (pre-treat with atropine)
179
What are the MOA of doxorubicin (per Chabner)? (6 things)
- activation of signal transduction pathways
- DNA intercalation
- generation of ROS
- inhibition of topoII
- stimulation of apoptosis
- perturbation of cell membrane
180
How do anthracyclines enter cells?
passive diffusion
181
What interactions occur between DOX and heparin, phenobarbital, Tylenol?
- heparin binds to DOX and increases clearance
- phenobarbital increases DOX clearance
- Tylenol diminishes hepatic reduced glutathione pools which sensitizes liver to anthracycline toxicity
182
What is the mechanism of DOX cardiotoxicity?
free radical damage to sarcoplasmic reticulum - decreased Ca binding, disrupts electrical excitation/contraction
Seen on bx: dilation of SR, disruption of myofibrils
183
What was incidence of cardiotox in dogs treated with DOX in Ratterree JAAHA 2012?
8%
7.4% arrhythmia, 2.1% cardiomyopathy
(Hallman - 15% high risk, 3% all comers; but it's a 2019 paper)
184
What is dexrazoxane?
iron chelator that prevents DOX induced lipid peroxidation and cardiotoxicity but doesn't significantly decrease anti-tumor activity
185
MOR to DOX?
- efflux pumps
- decreased topoII activity
- up regulation of O2 free radical defense (i.e. GSH)
- decreased sensitivity to apoptosis
- mutation in BER (PARP)
186
For DOX (regarding PK) - anti-tumor activity and myelosuppression are related to ____ while carditoxicity is related to ____.
AUC
| Cmax
187
Where is DOX excreted?
bile - decrease with liver dysfunction
188
What is the DLT of DOX in MDR1 mutant/mutant dogs? (Gustafson JVIM 2010)
```
GI toxicity (estimated recommended dose was 10.7 mg/m2 for gut)
dose reductions to prevent likely result in sub therapeutic concentrations
```
189
What is the MOA of mitoxantrone?
DNA intercalation
| inhibition of topoII
190
What were the results of adjuvant mitoxantrone in cats with mammary carcinoma? What were the AEs?
```
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
What % of dogs experienced AE when treated with epirubicin? What % were hospitalized?
Marrington VCO 2012
58% AEs - prophylactic meds did not avoid
24% hospitalization
(30 mg/m2 IV or 1 mg/kg if < 10kg)
192
What is the MTD and DLT of oral idarubicin in dogs?
Vail JVIM 2012
MTD 22 mg/m2 PO (given once)
DLT: myelosuppression
11/19 dogs with LSA responded
193
How does Doxil differ from doxorubicin?
pegylated miposomal form - addition of multiple polyethylene glycol groups extends half-life and restricts distribution
194
What unique toxicity is seen with Doxil? How can it be prevented/treated? What additional toxicity is seen in cats?
Poirier 2002
PPED (palmoplantar erythrodysesthesia) - Vit B6 (piridoxine); PPED shown to correlate with dose intensity
23% of cats had nephrotoxicity
195
What is the MOA of bleomycin?
activated Fe-bleomycin-O2 complex causes DNA cleavage
196
Why are skin and lungs sites of bleomycin toxicity?
it is degraded by enzyme bleomycin hydrolase and concentration in skin/lungs is low
197
What is route of excretion of bleomycin?
renal (decrease with renal dysfunction)
198
What unique routes of bleomycin administration have been explored in veterinary patients?
Kelly VCO 2010 - intralesional bleomycin for acanthomatous ameloblastoma
Spugnini JVIM 2015, Tozon JFMS 2014 - IV bleomycin in conjunction with electroporation for SCC
199
Bleomycin toxicities? (3)
pulmonary fibrosis
desquamation
HS reaction
200
What is the MOA of dactinomycin?
inhibition of RNA and protein synthesis
201
What is the RR for DMAC? Most common AE?
44% CR, 28% PR (72%)
| AEs: 56% thrombocytopenia, 17% neutropenia, 22% GI
202
In what tumor type has mitomycin C been studied in dogs?
Phase I intravesicular mitomycin C in TCC
5/13 PR, 2/13 severe myelosuppression
Abbo JVIM 2010
203
What drug (not a chemo) is excreted via Pgp?
ondansetron
204
What are two non-chemo drugs that can be used to inhibit MDR and therefore possibly increase efficacy of chemo drugs?
verapamil
| cyclosporine
205
Platinum agents in which configuration are clinically active?
cis (not trans)
206
Name the carrier ligand and leaving group for: cisplatin, carboplatin, oxaliplatin
cisplatin - chloride
carboplatin - carboxylate
oxaliplatin - oxalate
207
How are platinum agents transported in/out of cells?
CTR1 (copper transporter into cell)
| ATP7A and ATP7B (copper transporter out of cell)
208
Are platinum agents cell cycle specific?
No
209
How does the name of an mAb help you identify origin?
a. Omab = murine
b. Ximab = chimeric
c. Zumab = humanized
d. Umab = human
- Most anticancer AB have ‘tu’ or ‘tum’ in the name
210
All clinically active platinum compounds form ___ DNA adducts which is responsible for their cell-killing effect.
bifunctional
211
What specific adducts account for > 80% of total platinum-DNA damage? How are these adducts repaired?
N7 guanine and adenosine intrastrand adducts
| Repaired by NER - if repair doesn't occur, cell death
212
Four MOR to platinums?
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
Main/important toxicity of: cisplatin, carboplatin, oxaliplatin?
Cisplatin: nephrotoxic, emetogenic, ototoxic
Carboplatin: BM suppression
Oxaliplatin: cumulative peripheral neurotoxicity
214
T/F: Cisplatin displays extensive long-term protein-binding in many tissues.
True
215
Regarding PK parameters, the efficacy and toxicity of cisplatin directly relates to ____.
AUC
216
What is the effect of lithium carbonate on carbo-induced thrombocytopenia in dogs?
can increase neu and PLT by unknown mechanism
| no difference seen in dogs with/without lithium
217
Satraplatin in tumor-bearing dogs? MTD? DLT? (Selting JVIM 2011)
MTD: 35 mg/m2
DLT: myelosuppression - PLT before neuts!
41% bioavailable
218
Results of giving CTX by three different routes to cats? (Stroda 2017)
tolerated regardless of administration type
| AUC was lower for oral compared to IV or IP
219
How did neutropenia from FDA lomustine compare to compounded? (Burton JVIM 2016)
All dogs neutropenic from FDA
Only 25% neutropenia after compounded
potency from 5 compounding pharmacies ranged from 50-115%
220
What is the highest inadvertent CTX dose that a dog recovered from? (Finlay 2017)
2,303 mg/m2 over 21d
221
What % of dogs tend to have ELE on CCNU? How did Denamarin affect this percentage? (Skorupski JVIM 2011)
86% of dogs on CCNU with ELE
| In this study, CCNU alone - 84%, with Denamarin - 68%
222
What unique AE has been reported with high cumulative CCNU in a cat? (Skorupski 2008)
pulmonary fibrosis
223
SHC in dogs with Cytoxan - what % with furosemide had it vs. no furosemide? (Charney 2003)
9% w/out
1.2% with
(pretty sure this was bolus dosing)
224
Does metronomic temozolomide affect Tregs? (Denies 2016)
Not alone, Tregs decreased with mTMZ/CTX combo
225
What CRs were seen with metronomic chlorambucil? (Leach 2011)
MCT, STS, thyroid, HiSa
226
What is the dose recommended for mCTX? What effects seen in tumors? (Burton 2011)
15 mg/m2 daily (was compared to 12.5 mg/m2)
| decreased Tregs and decreased MVD in tumors
227
How does 1 mg/kg compare to 25 mg/m2 in cats with DOX? (Reiman 2008)
neuts significantly lower at 25 mg/m2 but tolerated
228
What is suramin? Results with DOX in phase I? (Kosarek 2006)
naphthalene anti-parasitic; nonspecific inhibitor of multiple growth factors including FGFs
improved response in 5 dogs who had DOX alone previously
229
What was MTD of idarubicin in dogs? DLT? What is idarubicin? (Vail 2012)
22 mg/m2
DLT: hematologic
anthracycline
230
What is elsamitrucin? MTD? DLT? (Fiocchi 2011)
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
Did furosemide help prevent SHC in dogs with mCTX? (Setyo 2017)
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
Which drugs are NOT affected by Pgp?
alkylating agents, antimetabolites, platinums
233
Which ABC transporter was associated with resistance in T cell LSA? (Zandvliet 2015)
ABCG2
| ABCB1 in B cell
234
Gemcitabine MTD and DLT? (Marconato 2015)
MTD 900 mg/m2
| DLT neutropenia
235
What unique toxicity did capecitabine cause in dogs?
corneal toxicity (superficial keratitis)
236
How were AE affected by prophylactic TMS with DOX? (Chretin 2007)
Dogs with TMS had reduced hospitalization, non-hematologic toxicity, GI toxicity, and reduced altered performance
(concluded that TMS reduced morbidity)
237
How did maropitant help with cisplatin induced emesis? (Vail 2007)
maropitant pre-med resulted in 94.9% of patients not vomiting compared to only 4.9% of controls
238
What is survivin? How did inhibitor affect LSA and OSA in vitro? (Thamm 2016)
inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis
inhibited growth, induced apoptosis, enhanced chemrsensitivity in vitro
239
MTD of pegylated TNFa? DLT? (Thamm 2010)
26.7 ug/kg
| DLT vascular leak and coagulopathy/hypotension
240
Why can cyclosporine help achieve lower doses of docetaxel?
docetaxel substrate of Pgp and metabolized by CYP3A
CSA modulates Pgp and CYP3A
docetaxel alone bioavailability 20% but approaches 100% with CSA
241
MTD of VBL? (Bailey 2008)
3.5 mg/m2
| neutropenia, sepsis, 1 death at this dose
242
MTD and DLT of carbo in cats? (Kisseberth 2008)
MTD 240 mg/m2
| DLT neutropenia
243
MTD of metformin in cats? (Wypij 2015)
10 mg/kg q12h
| DLT mild/moderate GI
244
How long were vinc, VBL, DOX, and CTX residues detected in urine after tx in dogs? (Knobloch 2010)
CTX - directly after tx but not subsequent days
Vinc - 3 days
VBL - 7 days
DOX - 21 days
245
What is the risk of exposure to chemo in blood samples 1 week after treatment? (Knobloch 2010)
Low risk, very few samples had detectable drug
246
How does Palladia cause PLN?
VEGFR inhibitors cause loss of healthy, fenestrated glomerular capillaries and possible disruption of podocyte integrity
247
How does Palladia cause hypertension?
VEGFR inhibition, increased endothelin-1
248
Masitinib dosing in cats? AE? (Daly 2011)
study did 50mg EOD vs. daily for 4 weeks
| 10% developed proteinuria, 15% neutropenia
249
Are patients <15 kg at increased risk for mitoxantrone neutropenia? (Richardson 2018)
Yes - and 46% of the patients developing neutropenia were hospitalized
250
What is Tavocept? How did it affect required diuresis in dogs with bladder tumors? (Henry 2018, Flesner on this paper)
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
What tumors showed response to hyaluronan-cisplatin nanoconaugate? (Can 2018, Flesner on paper)
SCC (3/7 had CR - both oral and nasal SCC)
252
What toxicity was seen with Palladia in cats? (Harper 2017)
10/14 - mild myelosuppression or GI effects
2 cats developed severe hepatotoxicity
1 cat developed CHF/death
253
5 toxicities to Palladia in cats.
thrombocytopenia, neutropenia, azotemia, hepatotoxicity, GI upset
254
MTD of CCNU with Palladia? DLT? ORR? (Pan 2014)
MTD of CCNU - 50 mg/m2 (with 2.75 mg/kg EOD Palladia)
DLT - neutropenia
ORR - 38.4%
255
What was elevated in serum of dogs receiving toceranib and CTX? (Mitchell 2012)
IFN-gamma, inversely correlated with Treg
256
Masitinib resulted in chemosensitization of HS to ____ and OSA and mammary CA to ____ and several other cancer cell lines too ____. (Thamm paper)
HS - VBL
OSA/mammary - Gem
others - DOX
257
How did masitinib reverse DOX resistance? (Zandvliet 2013)
Inhibit Pgp
258
What solid tumors showed clinical benefit from Palladia? (London 2011)
```
AGASACA (88%)
OSA (48%)
Thyroid (80%)
Head/neck (SCC) (88%)
Nasal carcinoma (71%)
```
Given at 2.8 mg/kg MWF
259
MTD of VBL with toceranib? Response rate? (Robat 2011)
VBL 1.6 m/m2 q2 weeks
toceranib was at 3.25 mg/kg EOD
Response rate 71%
260
What unique side effect has been reported with hydroxyurea? (Conrado 2017)
macrocytosis
| megaloblastic changes have been reported in multiple species with hydroxyurea
261
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)
29%
Three dogs (2.8% developed clinical hepatopathy)
Boxers at greater risk in this study
262
In the 2018 consensus statement, how many days after administration were the following drugs detected in urine?
- carboplatin
- CTX
- DOX
- VBL
- vincristine
- carboplatin: 21d (also looked at feces, alive, sebum, cerumen)
- CTX: 1-4d
- DOX: 21d
- VBL: 7d
- vincristine: 3d
263
How does 6-TG cause genomic demethylation?
reduction of DNMT1 protein through the ubiquitin-proteasome pathway
264
What was the biologic activity for Toceranib in the solid tumors publication? What was the objective response rate? (London 2013)
biologic: 74% - most SD
objective: 31.7%
265
Which tumors experienced a PR in the toceranib and coli tumors paper? (London 2013)
```
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
What toceranib targets have been identified in AGASACA and thyroid CA? Where in the cell/tumor are they expressed?
intracellular PDGFR-a in both
stromal PDGFR-B in both
intracellular VEGFR2 in both
267
What was biologic activity of TOC/VBL? (Robat 2011) How does this compare to single agent VBL and TOC?
Combination - 71% (2 CR, 8 PR)
| Alone: VBL - 12%, TOC - 43%
268
What % of dogs develop proteinuria with toceranib? (Tjostheim and Piscoya)
20% in these two retrospective studies
269
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
D
270
Which alkylating agents cross the cell membrane via active transport?
- mustargen
- chlorambucil
- carmustine
- melphalan
mustargen and melphalan
271
What specific adducts account for the majority of platinum-DNA damage?
N-7 guanine and adenine intrastrand adducts
