Chemo Flashcards
(298 cards)
1
Q
Which RTKs (5) does Palladia target
A
VEGFR2 PDGFR alpha + beta FLT3 KIT CSFR1
2
Q
Which classes of drugs are considered most potentially leukemogenic?
A
mustard-type alkylators
nitrosurias
procarbazine
3
Q
What is the aim of a Phase 0 trial?
A
quickly establish whether an agent displays biologic activity in humans
ie microdose PK, functional imaging
4
Q
What are the aims of a Phase 1 trial?
A
characterize toxicity
define dose/schedule
5
Q
What are the aims of a Phase 2 trial?
A
Detect biological efficacy
**historically, a 20% response rate was required to move to Phase III trials
6
Q
What is the aim of a Phase 3 trial?
A
Determine if investigational tx shows statistically and clinically important benefit over accepted standard of care
7
Q
What are the hallmarks of Phase 3 trial design?
A
Standard tx control group
Broad cohort of patients
Endpoints with relevance to patient
8
Q
What characterizes first order kinetics?
A
log[concentration] = linear fx of time
9
Q
What are Phase I reactions? Which is the most common?
A
Oxidation, reduction, and hydroplysis
Most common = P450 oxidation
10
Q
What are Phase II reactions? Which is the most common?
A
Conjugation
Most common = glucuronide conjugation by UGT
11
Q
What is the result of glucuronidation?
A
Detoxification - inactivates compound and facilitates biliary excretion
12
Q
Which pharmacokinetic parameter most closely equates to toxicity?
A
AUC
13
Q
In what form is folic acid an active coenzyme to DNA precursor synthesis, and which enzyme is required to catalyze formation of this coenzyme?
A
tetrahydrofolate (fully reduced)
DHFR catalyzes formation
14
Q
How does methotrexate inhibit DNA synthesis?
A
inhibition of thymidylate synthase/ purine biosynthesis
mostly due to accumulation of inactive folate residues and dihydrofolate polyglutamates (PGs)
15
Q
How does methotrexate enter the cell?
A
reduced folate carrier system
folate receptor
16
Q
What impact do low folate conditions have on methotrexate toxicity and why?
A
Increased toxicity due to upregulation of folate receptors and enhanced cellular accumulation
17
Q
How does leucovorin rescue work?
A
Overcomes enzyme inhibition by competitive displacement inactive folate PGs
Leucovorin = reduced folate; enters cell through same transport system as methotrexate
Given w/in 36hrs of treatment
18
Q
How is methotrexate excreted?
A
active urinary secretion in proximal tubules
some biliary excretion and EH recirculation
19
Q
What is the DLT of methotrexate?
A
GI toxicity, mucositis
20
Q
What causes methotrexate-induced AKI?
A
MTX precipitation in acidic urine
21
Q
What is the MOA of permatrexed?
A
TS inhibitor
22
Q
What is the MOA of Pralatrexate?
A
DHFR inhibitor
23
Q
When 5-FU is given prior to methotrexate, what impact does it have on methotrexate cytotoxicity?
A
Decreased cytotoxicity due to inhibition of TS by 5-FU
24
Q
How does 5-FU enter the cell, and how is it activated?
A
Facilitated transport
Metabolized to FUDP and FUTP
25
What is the MOA of 5-FU cytotoxicity?
Inhibition of TS
| Incorporation into RNA
26
What impact does methotrexate have on 5-FU activation?
Increased 5-FU activation because of increased cellular pools of PRPP
27
What impact do increased cellular pools of UTP and dUMP have on 5-FU toxicity?
Decreased toxicity
28
What impact does decreased MMR capability have on 5-FU toxicity?
Decreased toxicity
29
What is capecitabine?
Orally bioavailable 5-FU prodrug
30
5-FU has been associated with decreased clearance of which drugs?
Warfarin, phenytoin
31
What is the energetic equivalent of 1Gy?
1 Joule absorbed/kg tissue
32
In which phases of the cell cycle are cells most radioresponsive?
late G2/M
33
In which phases of the cell cycle are cells most radioresistant?
late S phase
34
What are the 5 Rs of RT?
```
DNA Repair
cell cycle Redistribution
Reoxygenation
Repopulation
Radiosensitization
```
35
When does accelerated repopulation occur?
After ~4wks of starting RT
36
What physiologic causes underly late radiation effects?
loss of stem cells
vascular changes
inflammation
**TGF-B
37
Which types of radiation are most likely to result in carcinogenesis?
orthovoltage
| high LET
38
On graph of radiation dose x surviving fraction, what do alpha and beta correspond to?
```
a = linear component, cell death that increases linearly with dose
B = quadratic component, cell death that increases in proportion to (dose)^2
```
39
On graph of radiation dose x surviving fraction, the curve for cells with a high a/B ratio appears:
Linear
40
On graph of radiation dose x surviving fraction, the curve for cells with a low a/B ratio appears:
Quadratic
41
At low-dose fractions, tissues/cells with a low a/B ratio are more or less resistant than those with a high a/B ratio?
Low a/B ratio = more resistant than high a/B ratio at low-dose fractionation schedules
42
Which bone is most susceptible to osteoradionecrosis?
Mandible
43
When do early delated effects to the CNS occur, and what do they correspond to pathophysiologically?
1-3 mo, transient demyelination
44
When do late delated effects to the CNS occur, and what do they correspond to pathophysiologically?
>6mo, brain necrosis
45
In a large series of palliative radiation therapy for solid tumors, what was the response rate? Rate of early and late toxicity?
RR - 75%
Early tox - 60%
Late tox - 8%
46
In a large series of palliative radiation therapy for solid tumors, which tumor types had the highest response rate?
AGASACA - 100%
STS - 87%
OSA - 85%
Tonsillar SCC - 80%
47
What were the average RT dose differences for GTV and OAR as calculated on pre- and post-contrast CT?
<1%
48
In a study of animals dogs undergoing RT with a cobalt-60 unit, significant reduction were identified in which CBC parameters throughout treatment?
Hct, WBC, neuts, eos, monos, lymphs
49
In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the ORR?
67% ORR, mPFS 5.7mo
50
In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the rate of acute toxicity?
17%
51
In a series of 51 dogs undergoing pelvic irradiation, what was the rate of late complications? Did this impact survival?
39%, did not impact survival
Most common = skin ulceration, draining tract, colitis, strictures
52
Which chemotherapy drugs should be dose reduced with hepatic dysfunction?
```
Vinca alkaloids
Paclitaxel
Etoposide
Busulfan
Imatinib
```
53
Which chemotherapy drugs should be dose-reduced in accordance with creatinine clearance in kidney dysfunction?
```
Carbo/cisplatin
Bleomycin
Etoposide
Methotrexate
Hydroxyurea
Topotecan
```
54
Which drugs can cause pleural effusion in cats?
Cisplatin
Docetaxel
Temozolomide
55
What unique toxicity does temozolomide cause in cats?
Pleural/pericardial effusion
56
What unique toxicity do cisplatin and 5-FU cause in cats?
Cisplatin - fatal pulmonary edema
| 5-FU - CNS toxicity
57
What antidote should be delivered following extravasation of mustargen?
Sodium thiosulfate SQ
Neutralizes mustargen to form nontoxic thioesters that are excreted in the urine
58
What complications may be seen with IP delivery of cyclophosphamide and vincristine in cats?
None
59
In dogs with OSA treated with adjuvant carboplatin, which factors were prognostic for decreased survival?
Proteinuria (pre-op)
Vascular invasion
MI >5/3hpf
Grade 3 tumors
60
How does the intracellular chloride concentration impact cisplatin activation?
- Cisplatin is activated by an aquation reaction, exchanging the 2 Cl leaving groups for H20
- High Cl concentration = no reaction = biologically inactive
- Intracellular concentrations of Cl are LOW compared to extracellular, so equation proceeds once cisplatin enters the cell
61
How does iohexol clearance correlate with carboplatin clearance?
Linear correlation
62
Which drug is more protein-bound: carboplatin or cisplatin?
Cisplatin > carboplatin protein binding
63
What is the DLT for idarubicin?
neutropenia, thrombocytopenia
64
What concerns arise with the use of denamarin and CCNU together?
Chemoresistance - SAMe and silybin are both potent antioxidants
65
```
Which of the following chemotherapy drugs may be detected in the urine up to 7d after administration?
CYC
Vincristine
Vinblastine
DOX
```
Vinblastine
| DOX (up to 21d)
66
What is the Calvert formula for carboplatin reduction?
Dose (mg) = target AUC x [GFR+25]
67
What is the recommended (weekly) starting dose of vinorelbine in dogs and cats? What are the DLTs?
Dogs - 15mg/m2; DLT = neutropenia
| Cats - 11.5mg/m2; DTL = neutropenia, vomiting, nephrotoxicity? (AKI in one cat)
68
What is the MTD of VBL when combined with 3.25mg/kg toceranib EOD?
1.6mg/m2 q2wk
69
How did the response rate and toxicity of a multiagent chemotherapy protocol with epirubicin compare to that of CHOP?
RR was equivalent/superior to previously published for CHOP
| toxicity was less than previously published for CHOP
70
What is the MOA of suramin?
Antiparasitic that inhibits reverse transcriptase and blocks growth factors
71
In a patient with renal and liver dysfunction, which of the following drugs could you administer without risk of increased toxicity?
methotrexate, vinca, DOX, mustargen, platinum
Mustargen (undergoes spontaneous hydrolysis)
Metabolized by liver: vinc, DOX
Excreted/potential for kidney damage: platinums
72
What drugs can be used in the case of liver failure?
Mustargen, fluorouracil, CYC
+/- oxalaplatins
NO taxanes, vincas anthracyclines, or ironotecan
73
Which drugs rely more on AUC than Cmax for efficacy?
Gemcitabine, Cytosar
74
What activates cisplatin?
Aquination (interaction with water)
75
Genetic polymorphisms in what gene can impact 5-FU toxicity, and why?
Dihydropyrimidine dehydrogenase (DPD) - catalyzes rate limiting step in 5-FU clearance
76
In a drug with first order pharmacokinetics, what happens to drug clearance as drug concentration increases?
Clearance increases linearly
77
In a drug with "zero order" pharmacokinetics, what happens to drug clearance as drug concentration increases?
Clearance remains the same - saturable clearance mechanism
78
What are the characteristics of cisplatin nephrotoxicity?
dose dependent acute tubular necrosis with azotemia and hypomagnesemia
79
What class of drugs does upregulation of MGMT increase resistance to?
Alkylators
80
What are the mechanisms of resistance to cisplatin?
Inactivation by glutathione
Increased NER
Decreased MMR
81
Which alkylators are bifunctional?
Melphalan
Chlorambucil
Cyclophosphamide/Ifosfamide
Mustargen
82
Which alkylators are monofunctional?
CCNU
Dacarbazine
Procarbazine
Streptozotocin
83
Does MESNA prevent ifosfamide-induced nephrotoxicity?
No - only cystitis by binding acrolein in the urine
84
How is ifosfamide activated?
P450 activation in liver - does NOT require intracellular activation
85
What metabolite of ifosfamide is neurotoxic?
Chloracetaldehyde - unique to ifosfamide
86
Which of the vincas has the highest tubulin affinity?
Vincristine
Inhibits tubulin polymerization even at very low concentrations
Also results in greater toxicity
87
Which topoisomerase isoform do epipodophylotoxins inhibit?
Topo-II
Etoposide & tenoposide = topoisomerase II inhibitors
88
What is the rate of docetaxel hypersensitivty in cats?
20% - ONLY when given IV (not when given orally), generally mild
89
What is the DLT of docetaxel in cats?
myelosuppression, GI
90
Why are cyclosporine and docetaxel given together?
CSA increases bioavailabilty of PO docetaxel
91
What is the DLT of satraplatin?
myelosuppression
thrombocytopenia occurs BEFORE neutropenia
GI tox was mild
92
Which of the following is more specific for kit inhibition?
Masitinib
Toceranib
Masitinib
93
Which of the following does masitinib inhibit with more efficacy?
WT kit
mutant kit
Inhibits both with similar efficacy
94
How might masitinib reverse DOX resistance?
Inhibition of PGP
95
Which four receptors does masitinib inhibit?
Kit
PDGFR
Lyn
FGFR
96
Which 3 receptors does imatinib ihibit?
BCR-Abl (ATP binding pocket of Abl)
Kit
PDGFR-alpha
97
What does bevacizumab bind?
VEGF
does NOT inhibit VEGFR directly
98
What is decitabine?
DNA methyltransferase inhibitor --> HYPOmethylating agent
May cause tumor progression due to genomic instability
99
How might decitabine increase wt-p53 expression?
Decitabine = hypomethylating agent
| Removes inhibitory methylation of p53 promoter
100
Other than vincas and taxanes, which drugs inhibit the mitotic spindle?
Griseofulvin
| Colchicine
101
What are Polo-like kinases (Plks)?
regulatory serine/threonine kinases involved in cell cycle:
mitotic entry, mitotic exit
spindle formation
cytokinesis, meiosis
102
Name 3 mitotic kinases.
Aurora
Polo-like
Bub
103
What impact does L-spar have on methotrexate?
Inactivation
104
How does rapamycin inhibit mTOR?
inhibits phosphorylation of AKT by direct binding to mTOR
105
What is the target of farnesyl transferase inhibitors?
HRAS inhibition
Farnesyl transferase inhibitors prevent post-translational modification of Ras
106
Aminobisphosphonates bind strongly to hydroxyapetite at which site?
R1, N1, R2, N2
R1
107
What is the active form of ara-C, and how is it activated?
ara-CTP
| activated intracellularly by phosphorylation
108
How is ara-C catabolized?
intracellular deactivation by cytidine deaminase to ara-U
109
Which two drugs are metabolized/inactivated by cytidine deaminase?
cytosar and gemcitabine
110
What impact does loss of ATR and Chk1 have on ara-C toxicity?
loss of ATR and Chk1 = increased ara-C toxicity
ATR and Chk1 block cell cycle progression and allow DNA repair
111
Ara-C is lipid or water soluble?
Water
112
With which agents is ara-C synergistic?
alkylating agents
methotrexate
etoposide
113
While GI toxicity and myelosuppression are the DLTs for ara-C, what unique toxicities can be seen with high-dose regimens?
Pulmonary toxicity
Cholestatic jaundice
Cerebellar toxicity
114
What are the mechanisms of action of ara-CTP?
Inhibition of DNApol-alpha
Incorporation into DNA
Termination of DNA chain elongation
115
What is the MOA of 5-Aza-Cytidine analogs such as aza and decitabine?
incorporate into DNA and inhibit DNA methylation
aka hypomethylating agents
116
What is the active form of gemcitabine, and which enzyme catalyzes the first step of this reaction?
dFdCMP
CdR catalyzes first phosphorylation step
117
What is the MOA of gemcitabine?
Inhibits DNApol & DNA repair
Incorporates into DNA
**Inhibits ribonucleotide reductase (this is where it differs from ara-C)
118
Which facet of gemcitabine MOA is implicated in its activity as a radiosensitizer?
Ribonucleotide reductase inhibition
119
How are gemcitabine and ara-C eliminated?
deamination in liver, plasma, and peripheral tissues by cytidine deaminase
120
What class of drug is 6-mercaptopurine?
Purine antimetabolite
121
Why does concurrent use of allopurinol increase 6-mercaptopurine bioavailability
Inhibits xanthine oxidase
6-MP is metabolized by intestinal xanthine oxidase, leading to significant first-pass effect
122
Which of the guanine analogs carries the highest risk of hepatotoxicity?
thioguanine
123
How is 6-mercaptopurine eliminated?
metabolism by xanthine oxidase and TPMT
124
How is thioguanine eliminated?
Hepatic metabolism
125
What is the MOA of 6-MP and thioguanine?
Incorporation of "fraudulent" nucleotides into DNA
6-MP also inhibits de novo purine synthesis
126
What is the MOA of fludarabine?
adenosine analog that incorporates into DNA
127
What is the MOA of pentostatin?
inhibition of adenosine deaminase --> accumulation of dATP
128
What is unique about the activity of cyclophosphamide and ifosfamide in relation to other alkylating agents?
Require metabolic activation by P450
129
What is the first step of the alkylation reaction?
Chlorine leaving group is lost, resulting in formation of reactive aziridinium ring
130
What DNA location do melphalan, busulfan and mechlorethamine alkylate?
N-7 guanine
melphalan also does adenine N-3
131
What DNA location do the nitrosureas, procarbazine, and DTIC alkylate?
O-6 methyl group of guanine
132
Which alkylators are bifunctional nitrogen mustards?
```
Meclorethamine
Melphalan
Chlorambucil
Cyclophosphamide
Ifosfamide
Bendamustine
```
133
Which alkylators are monofunctional nitrosureas?
CCNU
BCNU (carmustine)
atypical alkylators (procarb, DTIC) are most closely related to nitrosureas
134
Characterize the lipid solubility and CNS penetration of procarbazine and DTIC?
Highly lipid soluble, penetrate CNS
135
How are most alkylating agents degraded?
Hydrolysis of alkylating moiety
| aka alkylation of water
136
What accounts for the slow entry of bleomycin into cells?
Large size, cationic (charged)
137
Which drugs inhibit topoisomerase I?
topotecan & ironotecan
138
Does one- or two-electron reduction of DOX result in a more toxic metabolite?
One-electron reduction --> semiquinone radical
Two electron reduction results in an unstable compound that spontaneously degrades into less toxic metabolites
139
What interaction is expected between anthracyclines and PARP inhibitors?
Antagonism
140
What impact does genetic deficiency of thiopurine methyltransferase (TPMT) have on sensitivity to mercaptopurine and 6-TG?
Increased toxicity in individuals with TPMT deficiency
141
What is the primary toxicity of the guanine analog nalaabine?
Neurotoxicity
142
What is the MOA of hydroxyurea?
Inhibition of ribonucleotide reductase - this enzyme catalyzes the rate-limiting step in dNTP synthesis
Inhibition occurs via iron chelation and inactivation of tyrosyl radical
143
To which cell-cycle phase is the cytotoxic activity of hydroxyurea specific?
S phase
144
As part of its catabolism, hydroxyurea is converted to what potent ribonucleotide reductase inhibitor?
Nitric oxide
145
What enzyme is responsible for hydroxyurea degradation?
urease
146
What is the DLT of hydroxyurea?
myelosuppression
147
What is the oral bioavailability of hydroxyurea?
80-100%
148
What is the route of elimination of hydroxyurea?
Renal
149
Name 3 biological actions of vinca alkaloids outside of microtubule interaction?
Interference with:
- Amino acid transport
- DNA/RNA synthesis
- Protein/lipid metabolism
150
At what point do vincas and taxanes block mitosis?
metaphase/anaphase transition
151
What occurs at low and high concentrations of vinca alkaloids?
Low conc = interference with microtubule dynamics
| High conc = inhibits polymerization of tubulin
152
Rank the vinca alkaloids in order of their binding affinity for tubulin.
Vincristine > VinBLAstine > Vinorelbine > VFL
**does NOT determine antitumor activity, but does appear to correlate to neurotoxicity
153
Name 3 tissues in which ABCB1 is constitutively expressed?
Renal tubular epithelium, colonic mucosa, adrenal medulla
154
Which of the vinca alkaloids has the longest terminal half-life?
Vincristine
155
What is the route of elimination for all vinca alkaloids?
Hepatic metabolism and biliary excretion
156
Characterize the degree of binding of vinca alkaloids to plasma protein and blood elements such as platelets?
Highly protein-bound
| Bind plt and other blood elements with high affinity
157
What alterations in tubulin can result in resistance to vinca alkaloids?
```
Structural alterations in alpha and beta tubulin resulting in increased stability
Decreased expression of class III B tubulin
```
158
In which organ does vincristine accumulate to the greatest extent?
Spleen
159
What % of vincristine/metabolites is excreted in the urine?
~12%
160
Which of the following drugs is more extensively concentrated in tissues: vincristine or vinblastine?
vinblastine
161
Which of the vinca alkaloids is most lipophilic?
vinorelbine
162
What impact might concurrent treatment with erythromycin or itraconazole have on vincristine toxicity?
Increased toxicity due to CYP3A inhibition
163
What impact do taxanes have on intracellular tubulin concentration?
Decreased tubulin concentration due to stabilization of polymerized tubulin
164
Which of the ABC transporters is most important in conferring taxane resistance?
MDR1
165
What steps should be taken in the case of vincristine extravasation?
Heat/warm packing
| SQ hyaluronidase injection
166
What impact can L-spar have on vincristine clearance?
Decreased hepatic clearance --> increased toxicity
167
What is considered the DLT of vincristine? Of the other vincas?
vinc - neurotox
| others - myelosuppression
168
Characterize the degree of protein binding by taxanes.
Highly protein bound
169
What impact do increased levels of the beta-III tubulin isotype have on sensitivity to vincas and taxanes?
Taxanes - increased resistance
Vincas - increased sensitivity
B-III tubulin increases dynamic instability
170
For which of the following is the affinity of taxanes higher?
a) soluble tubulin
b) polymerized tubulin
Polymerized tubulin
171
Where is the primary taxane binding site?
N-terminal of B-tubulin subunit
172
What factors limit oral bioavailability of taxanes, and coadministration of which drug may help mitigate this?
Pgp/first-pass metabolism by liver/enterocytes
| Cyclosporine can help improve oral bioavailability
173
What cardiac symptoms are most commonly observed in association with taxane treatment?
Bradyarrythmias
174
How are taxanes eliminated
P450 metaboism and biliary/fecal excretion
| <10% in urine
175
MRP1 and MRP2 (ABCC1 and ABCC2) are more important in resistance to which of the microtubule-targeting agents?
Vincas
Limited contribution to taxane resistance
176
What is the DLT of paclitaxel?
neutropenia
177
Which infusion schedules increase the risk for paclitaxel-associated neurotoxicty?
short infusion schedules
178
What impact do mutations in KRAS or BRAF have on sensitivity to anti-EGFR therapies?
Decreased sensitivity - downstream activation
179
What were the two characteristics proposed as "emerging" hallmarks of cancer in Hannahan and Weinberg's 2011 review of the hallmarks of cancer?
Deregulated cellular energetics
| Avoiding immune destruction
180
What were the original 6 characteristics proposed as the hallmarks of cancer?
```
sustaining proliferative signaling
evading growth suppressors
enabling replicative immortality
activating invasion and metastasis
inducing angiogenesis
resisting cell death
```
181
What is a nucleophile?
Electron-rich atom
182
If a tumor shows resistance to a nitrogen mustard agent such as CYC, will it also exhibit resistance to a nitrosurea such as CCNU?
Not necessarily - nitrogen mustards and nitrosureas show only partial cross-resistance
183
Alkylation by alkylating agents is nonuniform along the length of the DNA strand. Which areas of DNA are most vulnerable to alkylation?
Regions of active transcription
184
Name two mechanisms of resistance with relevance to all alkylators?
glutathione inactivation
| enhanced DNA repair - esp DNA alkyltransferase
185
Decreased MMR results in decreased sensitivity/increased resistance to which classes of drugs?
5-FU
alkylators
methylators (DTIC, procarb)
platinums
186
What are the most common adducts formed by alkylating agents?
N3 methyladenine
| N7 methylguanine
187
What effect does increased BER function have on tumor cell sensitivity to alkylators?
Decreased sensitivity
188
What impact does xeroderma pigmentosum have on sensitivity to alkylating agents?
Increased sensitivity
Xeroderma pigmentosum = defective NER
189
What happens to cyclophosphamide metabolism and half-life over time (increases or decreases) with ongoing administration?
Metabolism increases, half-life decreases - both CYC and ifosfamide induce their own metabolism by P450 enzymes
190
How does 2-mercaptoethane sulfonate help to prevent acrolein-induced cystits without impacting anti-tumor activity?
MESNA dimerizes to inactive metabolite in plasma and hydrolyzes in urine to conjugate with acrolein
191
Name 3 features common to all atypical alkylators/methylating agents (ie procarb, DTIC).
lack bifunctionality
prodrugs that require activation
contain N-methyl group
192
Name 2 mechanisms of resistance that impact sensitivity to all methylating agents.
AGT-mediated O6 methylguanine repair
| MMR deficiency
193
What impact does the activity of AGT have on sensitivity to procarbazine? CCNU?
Decreased sensitivity/increased resistance
AGT functions in O6 methylguanine repair - increases resistance to methylators and nitrosureas
194
By what route are procarb and DTIC eliminated?
Renal excretion
195
What is the common metabolite generated by both DTIC and temozolamide under physiologic conditions?
MTIC --> AIC
196
Which of the atypical alkylators penetrate the BBB?
Procarb
Temozolomide
NOT dtic
197
What is the oral bioavailability of CYC, melphalan, and busulfan?
CYC - 100%
melphalan - 30% (variable)
busulfan >50%
198
What proportion of CYC, ifosfamide, and melphalan is excreted into the urine unchanged?
CYC/ifos - NONE - only inactive oxidation products excreted
| Melphalan - 20-35%
199
What is the DLT of IV procarbazine? What is the efficacy of IV procarbazine compared to oral dosing?
DLT = neurotoxicity
Lack of efficacy due to need for first-pass metabolism and drug activation
200
To what extent is DTIC protein-bound in plasma?
~20% loosely protein-bound
201
What percentage of DTIC is eliminated unchanged in the urine?
~50%
202
How is temozolomide converted to its active metabolite?
Spontaneous conversion on interaction with water, especially at alkaline pH >7.0
203
Which enzyme constitutes the primary mechanism of resistance to temozolomide?
AGT
204
Cisplatin's chloride leaving group is much simpler than that of carbo or oxaliplatin -- what impact does this have on its reactivity, passage through membranes, and toxicity relative to other platinum drugs?
Greater reactivity in aqueous solution
Crosses membranes more readily
Greater toxicity
205
Platinums have higher affinity for which nucleic acid? Interactions with DNA or RNA account for most of their cytotoxicty?
higher affinity for RNA, but most toxic effects come from DNA
206
What is the predominant DNA repair pathway used to repair platinum-induced DNA lesions?
ds break repair (ie NHEJ, HR)
207
What is amofostine?
A disulfide preferential activated in normal cells to scavenge free radicals -- can be used to prevent cisplatin-associated neurotoxicity.
208
What is the preferred solution for cisplatin injection?
normal saline
**avoid Mg++ containing fluids and aluminum needles as these mat inactivate cisplatin
209
What is the Calvert formula for carboplatin dosing?
dose = target AUC * (GFR + 25)
210
What DNA lesions are formed by platinums?
Bifunctional DNA adducts which result in kinking of DNA due to rigid bond angles
211
What DNA lesions does bleomycin result in?
Direct DNA damage --> intercalation, ss and ds breaks
212
In which phases of the cell cycle is DNA most sensitive to cleavage by bleomycin?
G2/M, and G1
213
Is bleomycin a substrate for Pgp/MDR1?
no
214
How is bleomycin excreted?
Urinary
215
Name 3 factors that increase risk for bleomycin-induced pulmonary toxicity.
- previous RT to chest
- cumulative dose >450U
- renal dysfunction
- age
216
Which cytokines are implicated in bleomycin-induced pulmonary toxicity?
TGF-B
TNF-a
IL-1B
IL2, 3, 4, 5, 6
217
How does anthracycline dosing schedule impact efficacy? Toxicity?
No impact of dosing schedule on efficacy - this depends on AUC
Shorter infusion times --> greater toxicity - this depends on Cmax
218
What is the MOA of dactinomycin?
inhibition of RNA & protein synthesis by binding to DNA
219
Is dactinomycin a substrate for Pgp?
Yes
220
What is the MOA of topotecan and ironotecan?
Topo-I poison - stabilizes cleavable complex
221
What is the DLT of topotecan and ironotecan?
neutropenia, thrombocytopenia
| GI/diarrhea - ironotecan >>> topotecan
222
What impact does an acidic microenvironment have of cell entry of DOX?
Acidic env't --> DOX becomes ionized
If EC acidosis --> ionization and accumulation outside cell
If IC acidosis --> accumulation within cell
223
How is mechlorethamine degraded?
Spontaneous degradation
224
What are the steps in CYC metabolism?
Activation in the liver to 4-OHCP
Spontaneous reversible ring opening to aldehyde aldophosphamide
Spontaneous irreversible breakdown of aldophosphamide to phosphoramide mustard and acrolein
225
What is the most active CYC metabolite?
Phosphoramide mustard
226
What is the major difference between CYC and ifosfamide metabolism, and how does this relate to toxicity?
Decloroethylation occurs much more frequently in ifosfamide (up to 25%) --> formation of neurotoxic choroacetaldehyde
227
What is the primary metabolite of chorlambucil?
phenylacetic acid
228
Why is DTIC use discouraged in cats?
Lack of information regarding their ability to convert the drug to active form
229
What percentage of dactinomycin is excreted unchanged in urine and feces?
20% urine
| 14% feces
230
What do one- and two-electron reduction of DOX result in?
One-electron reduction --> semiquinone free radical --> H2O2
| Two-electron --> less toxic metabolites
231
Why is the activity of dexrazoxane increased in cardiac myocytes compared to other tissues?
greatly increased conversion of prodrug to active iron chelator
232
What impact do increased Bcl-2 expression and NFkB expression have on DOX sensitivity?
Decreased sensitivity/ increased resistance due to resistance to apoptosis (Bcl-2) and improved cellular response to stress (NFkB)
233
DOX is a substrate for which efflux pumps?
MDR1
| MRP
234
What is the primary mode of DOX excretion?
Biliary
235
What impact does paclitaxel administration have on DOX clearance?
delayed, likely due to Cremophor which is a substrate for Pgp
236
What impact does coadministration of traztuzumab have on risk for DOX-induced cardiotoxicity?
increased risk
237
What is the most cardiotoxic metabolite of DOX?
Doxorubicinol
238
How do anthracyclines enter the cell?
Diffusion of un-ionized drug
239
What impact does reduction in topoisomerase II activity have on DOX resistance?
decreased topo-II activity --> increased resistance to DOX & other topo-II inhibitors
240
What impact would increased cellular levels of topoisomerase II have on sensitivity to etoposide?
Increased sensitivity
241
What type of DNA breaks do topoisomerase I and III result in?
ssDNA breaks (Type I topoisomerases)
242
What type of DNA breaks does topoisomerase II result in?
dsDNA breaks
243
What change in etoposide dosing should be made in patients with renal dysfunction?
dose decrease - ~40% etoposide is eliminated by kidneys
244
Does etoposide function as a radiation sensitizer?
yes
245
What is the result of coadministration of etoposide and platinum drugs?
Highly synergistic
246
L-spar catalyzes hydrolysis of asparagine to which end products?
aspartic acid + ammonia
247
What impact does L-spar have on methotrexate activity?
terminates action of methotrexate
248
What is the MOA of first-generation bisphosphonates such as etidronate and clodronate?
metabolized to cytotoxic analogs of ATP
249
What is the MOA nitrogen-containing bisphophonates (risendronate, pamidronate, and zolendronate)?
- inhibit farnesyl diphosphate synthase, a mevalonate pathway protein, decreasing prenylation of essential GTP-binding proteins
- increase osteoblast secretion of an inhibitor of osteoclat recruitment
- increase osteoblast secretion of TGF-B, a signal for osteoblast apoptosis
250
Which side chain determines bisphosphonate antiresorptive potency?
R2 side chain
251
Characterize the oral bioavailabiltiy of bisphosphonates.
Poor (<1%) due to calcium binding
252
How are bisphosphonates metabolized and excreted?
they are NOT metabolized - P-C backbone is resistant to hydrolysis
excreted through kidneys
253
What accounts for bisphosphonate binding to hydroxyapetite?
R1 side chain
254
What deterines bisphosphonate-induced renal toxicity?
R1 side chain - related to high total dose, short infusion time, and decreased baseline renal function
255
Which drugs are substrates for all 3 major drug efflux pumps (Pgp, MRP1, and BCRP)?
DOX/daunorubicin
| methotrexate
256
Vincristine, vinblastine, etoposide and paclitaxel are substrates for which drug efflux pumps?
Pgp
| MRP1
257
For which drug efflux pumps is mitoxantrone a substrate?
Pgp
| BCRP/ABCG2
258
What is the target of lapatinib?
HER2 + EGFR
259
Which targeted therapy are nonsmoking women (especially those of Asian decent) with lung carcinoma most likely to respond to?
EGFR inhibitors - gefitinib and erlotinib
260
What is the target for rapamycin?
TORC1
261
What is the target of sorafenib?
RET, VEGFR
262
Which family of kinases are the primary effectors of inflammatory cytokine receptor signaling?
JAK
JAK2 inhibitors are used in myeloproliferative diseases in people
263
What is the target of crizotinib?
ALK (anaplastic lymphoma kinase)
264
Activating point mutations in which gene result in the hereditary multiple endocrine neoplasia type 2?
RET
265
What is ipilimumab?
anti-CTLA-4 mAb
266
What toxicities limited the utility of hyaluronan cisplatin nanoconjugate in dogs with SCC?
Severe myelosuppression, cardiotoxicity, and ALT elevations
267
What was the DLT of oral PPARg agonist rosiglitazone?
hepatic - ALT elevation
268
What does formulation of therapeutic proteins with polyethylene glycol (PEG) achieve?
Increased circulating half-life
| Decreased immunogenicity
269
What was the MTD of PEGylated TNFa in dogs with various tumors?
26.7 ug/kg
DLT = vascular leak, hypotension, coagulopathy
minor/transient tumor responses noted in various tumor types
270
What is valproic acid and what can be used as a pharmacodynamic biomarker for its activity?
HDACi
histone hyperacetylation in circulating PBMCs
**valproic acid was well tolerated in dogs, MTD not reached
271
What clinical factors were associated with prolonged hospital stay in febrile neutropenic canine chemo patients?
tachycardia at admission
comorbidities
G-CSF use
decreasing neutrophil count after admission
272
What was the mortality rate and what factors were associated with death in-hospital in febrile neutropenic canine chemo patients?
8.5%
| hypotension, G-CSF use
273
What was the rate of GI toxicity & creatinine elevation from baseline in dogs receiving piroxicam? Which factors increased risk of these toxicities?
GI - 84% - age and GI protectants increased risk
Creat - 73% - TCC increased risk
274
What was the incidence of SHC after CYC given orally over 3 days?
0%
historical values - 11% for single dose, 1.4% for single + furosemide
275
Increased LEs occurred in what %s of dogs receiving CCNU alone vs CCNU with denamarin?
84% vs 68%
dogs w/o SAMe had significantly greater increases in liver values and were more likely to have tx delayed or discontinued
276
What was the response to plasmid GHRH electroporation to treat cancer-associated anemia in dogs?
Up to 54% had increased Hct, and responders had significantly longer survival
277
How long is platinum detectable in canine urine, feces, saliva, sebum, and cerum by mass spec following administration?
at least 21 d
278
What was the MTD of vinorelbine in cats?
11.5mg/m2
279
What % of cats were euthanized due to toxicity in a pilot study of temozolomide +/- DOX?
40% :(
1 due to prolonged myelosuppression, 1 due to pleural/pericardial effusion (apparently cumulative toxicity >1300mg/m2)
280
What was the rate of hepatotoxicity in cats treated with CCNU?
6.8%
281
What proportion of cats had DPD activity values indicating decreased activity? Is decreased DPD activity thought to account for unique 5-FU toxicity in this species?
23% - not thought to account for 5-FU tox
In another study, 14% of dogs with abnormal
282
What was the rate of AEs in a large series of dogs treated with epirubicin?
36% of treatments
283
What is the MTD of idarubicin in dogs >15kg?
22mg/m2
284
What was the RR of epithelial neoplasia to oral docetaxel + CSA?
17%
50% RR for OSCC
285
What is the MTD of Paccal Vet in dogs?
150mg/m2
286
Dogs with MCT treated with Paccal Vet were ___x more likely to have a response than those treated with CCNU?
6.5X
RR = 7% (23% BRR)
287
What was the MTD of a single bolus gemcitabine dose in dogs?
900mg/m2
Undetectable in urine at 24hrs
288
Metronomic CCNU was discontinued in what % of patients due to toxicity? When was hepatotoxicity recongized?
27%
hepatotox at median 11d
289
What % dogs developed hypertension following treatment with Palladia?
37%
290
What was the MTD of CCNU + Palladia?
50mg/m2 q3wks
291
What is the MTD of toceranib + piroxicam?
Full dose of both
292
What was the ORR of canine MCT to toceranib + VBL?
71%
293
Which combinations of bisphosphonates and chemotherapy drugs elicited synergistic killing in histiocytic sarcoma cell lines?
clodronate + vinc
| zol + DOX
294
What is the genotype of the ABCB1 polymorphism in dogs?
4 base-pair deletion resulting in a reading frame shift and premature stop codons
295
Other than the BBB, what privileged sites does PGP participate in maintaining?
blood-testes barrier
| placenta
296
Other than the BBB, what privileged sites does BCRP (ABCG2) participate in maintaining?
retina - this is thought to underly fluoroquinolone-induced blindness in cats
297
What is the function of feline ABCG2 compared to humans?
decreased
298
What is the MTD of DOX in horses?
75mg/m2 q3wks
DLT = hypersensitivity and neutropenia
