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Onco Board Review > Chemo > Flashcards

Chemo Flashcards

1
Q

Which RTKs (5) does Palladia target

A 
VEGFR2
PDGFR alpha + beta
FLT3
KIT
CSFR1
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2
Q

Which classes of drugs are considered most potentially leukemogenic?

A

mustard-type alkylators
nitrosurias
procarbazine

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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

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4
Q

What are the aims of a Phase 1 trial?

A

characterize toxicity

define dose/schedule

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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

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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

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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

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8
Q

What characterizes first order kinetics?

A

log[concentration] = linear fx of time

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9
Q

What are Phase I reactions? Which is the most common?

A

Oxidation, reduction, and hydroplysis

Most common = P450 oxidation

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10
Q

What are Phase II reactions? Which is the most common?

A

Conjugation

Most common = glucuronide conjugation by UGT

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11
Q

What is the result of glucuronidation?

A

Detoxification - inactivates compound and facilitates biliary excretion

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12
Q

Which pharmacokinetic parameter most closely equates to toxicity?

A

AUC

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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

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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)

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15
Q

How does methotrexate enter the cell?

A

reduced folate carrier system

folate receptor

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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

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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

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18
Q

How is methotrexate excreted?

A

active urinary secretion in proximal tubules

some biliary excretion and EH recirculation

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19
Q

What is the DLT of methotrexate?

A

GI toxicity, mucositis

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20
Q

What causes methotrexate-induced AKI?

A

MTX precipitation in acidic urine

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21
Q

What is the MOA of permatrexed?

A

TS inhibitor

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22
Q

What is the MOA of Pralatrexate?

A

DHFR inhibitor

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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

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24
Q

How does 5-FU enter the cell, and how is it activated?

A

Facilitated transport

Metabolized to FUDP and FUTP

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25
Q

What is the MOA of 5-FU cytotoxicity?

A

Inhibition of TS

Incorporation into RNA

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26
Q

What impact does methotrexate have on 5-FU activation?

A

Increased 5-FU activation because of increased cellular pools of PRPP

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27
Q

What impact do increased cellular pools of UTP and dUMP have on 5-FU toxicity?

A

Decreased toxicity

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28
Q

What impact does decreased MMR capability have on 5-FU toxicity?

A

Decreased toxicity

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29
Q

What is capecitabine?

A

Orally bioavailable 5-FU prodrug

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30
Q

5-FU has been associated with decreased clearance of which drugs?

A

Warfarin, phenytoin

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31
Q

What is the energetic equivalent of 1Gy?

A

1 Joule absorbed/kg tissue

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32
Q

In which phases of the cell cycle are cells most radioresponsive?

A

late G2/M

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33
Q

In which phases of the cell cycle are cells most radioresistant?

A

late S phase

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34
Q

What are the 5 Rs of RT?

A 
DNA Repair
cell cycle Redistribution
Reoxygenation
Repopulation
Radiosensitization
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35
Q

When does accelerated repopulation occur?

A

After ~4wks of starting RT

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36
Q

What physiologic causes underly late radiation effects?

A

loss of stem cells
vascular changes
inflammation
**TGF-B

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37
Q

Which types of radiation are most likely to result in carcinogenesis?

A

orthovoltage

high LET

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38
Q

On graph of radiation dose x surviving fraction, what do alpha and beta correspond to?

A 
a = linear component, cell death that increases linearly with dose
B = quadratic component, cell death that increases in proportion to (dose)^2
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39
Q

On graph of radiation dose x surviving fraction, the curve for cells with a high a/B ratio appears:

A

Linear

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40
Q

On graph of radiation dose x surviving fraction, the curve for cells with a low a/B ratio appears:

A

Quadratic

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41
Q

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?

A

Low a/B ratio = more resistant than high a/B ratio at low-dose fractionation schedules

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42
Q

Which bone is most susceptible to osteoradionecrosis?

A

Mandible

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43
Q

When do early delated effects to the CNS occur, and what do they correspond to pathophysiologically?

A

1-3 mo, transient demyelination

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44
Q

When do late delated effects to the CNS occur, and what do they correspond to pathophysiologically?

A

> 6mo, brain necrosis

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45
Q

In a large series of palliative radiation therapy for solid tumors, what was the response rate? Rate of early and late toxicity?

A

RR - 75%
Early tox - 60%
Late tox - 8%

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46
Q

In a large series of palliative radiation therapy for solid tumors, which tumor types had the highest response rate?

A

AGASACA - 100%
STS - 87%
OSA - 85%
Tonsillar SCC - 80%

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47
Q

What were the average RT dose differences for GTV and OAR as calculated on pre- and post-contrast CT?

A

<1%

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48
Q

In a study of animals dogs undergoing RT with a cobalt-60 unit, significant reduction were identified in which CBC parameters throughout treatment?

A

Hct, WBC, neuts, eos, monos, lymphs

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49
Q

In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the ORR?

A

67% ORR, mPFS 5.7mo

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50
Q

In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the rate of acute toxicity?

A

17%

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51
Q

In a series of 51 dogs undergoing pelvic irradiation, what was the rate of late complications? Did this impact survival?

A

39%, did not impact survival

Most common = skin ulceration, draining tract, colitis, strictures

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52
Q

Which chemotherapy drugs should be dose reduced with hepatic dysfunction?

A 
Vinca alkaloids
Paclitaxel
Etoposide
Busulfan
Imatinib
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53
Q

Which chemotherapy drugs should be dose-reduced in accordance with creatinine clearance in kidney dysfunction?

A 
Carbo/cisplatin
Bleomycin
Etoposide
Methotrexate
Hydroxyurea
Topotecan
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54
Q

Which drugs can cause pleural effusion in cats?

A

Cisplatin
Docetaxel
Temozolomide

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55
Q

What unique toxicity does temozolomide cause in cats?

A

Pleural/pericardial effusion

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56
Q

What unique toxicity do cisplatin and 5-FU cause in cats?

A

Cisplatin - fatal pulmonary edema

5-FU - CNS toxicity

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57
Q

What antidote should be delivered following extravasation of mustargen?

A

Sodium thiosulfate SQ

Neutralizes mustargen to form nontoxic thioesters that are excreted in the urine

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58
Q

What complications may be seen with IP delivery of cyclophosphamide and vincristine in cats?

A

None

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59
Q

In dogs with OSA treated with adjuvant carboplatin, which factors were prognostic for decreased survival?

A

Proteinuria (pre-op)
Vascular invasion
MI >5/3hpf
Grade 3 tumors

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60
Q

How does the intracellular chloride concentration impact cisplatin activation?

A
  • 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
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61
Q

How does iohexol clearance correlate with carboplatin clearance?

A

Linear correlation

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62
Q

Which drug is more protein-bound: carboplatin or cisplatin?

A

Cisplatin > carboplatin protein binding

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63
Q

What is the DLT for idarubicin?

A

neutropenia, thrombocytopenia

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64
Q

What concerns arise with the use of denamarin and CCNU together?

A

Chemoresistance - SAMe and silybin are both potent antioxidants

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65
Q 
Which of the following chemotherapy drugs may be detected in the urine up to 7d after administration?
CYC
Vincristine
Vinblastine
DOX
A

Vinblastine

DOX (up to 21d)

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66
Q

What is the Calvert formula for carboplatin reduction?

A

Dose (mg) = target AUC x [GFR+25]

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67
Q

What is the recommended (weekly) starting dose of vinorelbine in dogs and cats? What are the DLTs?

A

Dogs - 15mg/m2; DLT = neutropenia

Cats - 11.5mg/m2; DTL = neutropenia, vomiting, nephrotoxicity? (AKI in one cat)

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68
Q

What is the MTD of VBL when combined with 3.25mg/kg toceranib EOD?

A

1.6mg/m2 q2wk

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69
Q

How did the response rate and toxicity of a multiagent chemotherapy protocol with epirubicin compare to that of CHOP?

A

RR was equivalent/superior to previously published for CHOP

toxicity was less than previously published for CHOP

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70
Q

What is the MOA of suramin?

A

Antiparasitic that inhibits reverse transcriptase and blocks growth factors

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71
Q

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

A

Mustargen (undergoes spontaneous hydrolysis)

Metabolized by liver: vinc, DOX
Excreted/potential for kidney damage: platinums

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72
Q

What drugs can be used in the case of liver failure?

A

Mustargen, fluorouracil, CYC
+/- oxalaplatins

NO taxanes, vincas anthracyclines, or ironotecan

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73
Q

Which drugs rely more on AUC than Cmax for efficacy?

A

Gemcitabine, Cytosar

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74
Q

What activates cisplatin?

A

Aquination (interaction with water)

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75
Q

Genetic polymorphisms in what gene can impact 5-FU toxicity, and why?

A

Dihydropyrimidine dehydrogenase (DPD) - catalyzes rate limiting step in 5-FU clearance

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76
Q

In a drug with first order pharmacokinetics, what happens to drug clearance as drug concentration increases?

A

Clearance increases linearly

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77
Q

In a drug with “zero order” pharmacokinetics, what happens to drug clearance as drug concentration increases?

A

Clearance remains the same - saturable clearance mechanism

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78
Q

What are the characteristics of cisplatin nephrotoxicity?

A

dose dependent acute tubular necrosis with azotemia and hypomagnesemia

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79
Q

What class of drugs does upregulation of MGMT increase resistance to?

A

Alkylators

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80
Q

What are the mechanisms of resistance to cisplatin?

A

Inactivation by glutathione
Increased NER
Decreased MMR

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81
Q

Which alkylators are bifunctional?

A

Melphalan
Chlorambucil
Cyclophosphamide/Ifosfamide
Mustargen

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82
Q

Which alkylators are monofunctional?

A

CCNU
Dacarbazine
Procarbazine
Streptozotocin

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83
Q

Does MESNA prevent ifosfamide-induced nephrotoxicity?

A

No - only cystitis by binding acrolein in the urine

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84
Q

How is ifosfamide activated?

A

P450 activation in liver - does NOT require intracellular activation

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85
Q

What metabolite of ifosfamide is neurotoxic?

A

Chloracetaldehyde - unique to ifosfamide

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86
Q

Which of the vincas has the highest tubulin affinity?

A

Vincristine

Inhibits tubulin polymerization even at very low concentrations
Also results in greater toxicity

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87
Q

Which topoisomerase isoform do epipodophylotoxins inhibit?

A

Topo-II

Etoposide & tenoposide = topoisomerase II inhibitors

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88
Q

What is the rate of docetaxel hypersensitivty in cats?

A

20% - ONLY when given IV (not when given orally), generally mild

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89
Q

What is the DLT of docetaxel in cats?

A

myelosuppression, GI

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90
Q

Why are cyclosporine and docetaxel given together?

A

CSA increases bioavailabilty of PO docetaxel

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91
Q

What is the DLT of satraplatin?

A

myelosuppression

thrombocytopenia occurs BEFORE neutropenia
GI tox was mild

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92
Q

Which of the following is more specific for kit inhibition?
Masitinib
Toceranib

A

Masitinib

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93
Q

Which of the following does masitinib inhibit with more efficacy?
WT kit
mutant kit

A

Inhibits both with similar efficacy

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94
Q

How might masitinib reverse DOX resistance?

A

Inhibition of PGP

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95
Q

Which four receptors does masitinib inhibit?

A

Kit
PDGFR
Lyn
FGFR

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96
Q

Which 3 receptors does imatinib ihibit?

A

BCR-Abl (ATP binding pocket of Abl)
Kit
PDGFR-alpha

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97
Q

What does bevacizumab bind?

A

VEGF

does NOT inhibit VEGFR directly

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98
Q

What is decitabine?

A

DNA methyltransferase inhibitor –> HYPOmethylating agent

May cause tumor progression due to genomic instability

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99
Q

How might decitabine increase wt-p53 expression?

A

Decitabine = hypomethylating agent

Removes inhibitory methylation of p53 promoter

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100
Q

Other than vincas and taxanes, which drugs inhibit the mitotic spindle?

A

Griseofulvin

Colchicine

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101
Q

What are Polo-like kinases (Plks)?

A

regulatory serine/threonine kinases involved in cell cycle:
mitotic entry, mitotic exit
spindle formation
cytokinesis, meiosis

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102
Q

Name 3 mitotic kinases.

A

Aurora
Polo-like
Bub

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103
Q

What impact does L-spar have on methotrexate?

A

Inactivation

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104
Q

How does rapamycin inhibit mTOR?

A

inhibits phosphorylation of AKT by direct binding to mTOR

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105
Q

What is the target of farnesyl transferase inhibitors?

A

HRAS inhibition

Farnesyl transferase inhibitors prevent post-translational modification of Ras

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106
Q

Aminobisphosphonates bind strongly to hydroxyapetite at which site?
R1, N1, R2, N2

A

R1

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107
Q

What is the active form of ara-C, and how is it activated?

A

ara-CTP

activated intracellularly by phosphorylation

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108
Q

How is ara-C catabolized?

A

intracellular deactivation by cytidine deaminase to ara-U

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109
Q

Which two drugs are metabolized/inactivated by cytidine deaminase?

A

cytosar and gemcitabine

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110
Q

What impact does loss of ATR and Chk1 have on ara-C toxicity?

A

loss of ATR and Chk1 = increased ara-C toxicity

ATR and Chk1 block cell cycle progression and allow DNA repair

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111
Q

Ara-C is lipid or water soluble?

A

Water

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112
Q

With which agents is ara-C synergistic?

A

alkylating agents
methotrexate
etoposide

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113
Q

While GI toxicity and myelosuppression are the DLTs for ara-C, what unique toxicities can be seen with high-dose regimens?

A

Pulmonary toxicity
Cholestatic jaundice
Cerebellar toxicity

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114
Q

What are the mechanisms of action of ara-CTP?

A

Inhibition of DNApol-alpha
Incorporation into DNA
Termination of DNA chain elongation

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115
Q

What is the MOA of 5-Aza-Cytidine analogs such as aza and decitabine?

A

incorporate into DNA and inhibit DNA methylation

aka hypomethylating agents

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116
Q

What is the active form of gemcitabine, and which enzyme catalyzes the first step of this reaction?

A

dFdCMP

CdR catalyzes first phosphorylation step

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117
Q

What is the MOA of gemcitabine?

A

Inhibits DNApol & DNA repair
Incorporates into DNA
**Inhibits ribonucleotide reductase (this is where it differs from ara-C)

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118
Q

Which facet of gemcitabine MOA is implicated in its activity as a radiosensitizer?

A

Ribonucleotide reductase inhibition

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119
Q

How are gemcitabine and ara-C eliminated?

A

deamination in liver, plasma, and peripheral tissues by cytidine deaminase

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120
Q

What class of drug is 6-mercaptopurine?

A

Purine antimetabolite

121
Q

Why does concurrent use of allopurinol increase 6-mercaptopurine bioavailability

A

Inhibits xanthine oxidase

6-MP is metabolized by intestinal xanthine oxidase, leading to significant first-pass effect

122
Q

Which of the guanine analogs carries the highest risk of hepatotoxicity?

A

thioguanine

123
Q

How is 6-mercaptopurine eliminated?

A

metabolism by xanthine oxidase and TPMT

124
Q

How is thioguanine eliminated?

A

Hepatic metabolism

125
Q

What is the MOA of 6-MP and thioguanine?

A

Incorporation of “fraudulent” nucleotides into DNA

6-MP also inhibits de novo purine synthesis

126
Q

What is the MOA of fludarabine?

A

adenosine analog that incorporates into DNA

127
Q

What is the MOA of pentostatin?

A

inhibition of adenosine deaminase –> accumulation of dATP

128
Q

What is unique about the activity of cyclophosphamide and ifosfamide in relation to other alkylating agents?

A

Require metabolic activation by P450

129
Q

What is the first step of the alkylation reaction?

A

Chlorine leaving group is lost, resulting in formation of reactive aziridinium ring

130
Q

What DNA location do melphalan, busulfan and mechlorethamine alkylate?

A

N-7 guanine

melphalan also does adenine N-3

131
Q

What DNA location do the nitrosureas, procarbazine, and DTIC alkylate?

A

O-6 methyl group of guanine

132
Q

Which alkylators are bifunctional nitrogen mustards?

A 
Meclorethamine
Melphalan
Chlorambucil
Cyclophosphamide
Ifosfamide
Bendamustine
133
Q

Which alkylators are monofunctional nitrosureas?

A

CCNU
BCNU (carmustine)

atypical alkylators (procarb, DTIC) are most closely related to nitrosureas

134
Q

Characterize the lipid solubility and CNS penetration of procarbazine and DTIC?

A

Highly lipid soluble, penetrate CNS

135
Q

How are most alkylating agents degraded?

A

Hydrolysis of alkylating moiety

aka alkylation of water

136
Q

What accounts for the slow entry of bleomycin into cells?

A

Large size, cationic (charged)

137
Q

Which drugs inhibit topoisomerase I?

A

topotecan & ironotecan

138
Q

Does one- or two-electron reduction of DOX result in a more toxic metabolite?

A

One-electron reduction –> semiquinone radical

Two electron reduction results in an unstable compound that spontaneously degrades into less toxic metabolites

139
Q

What interaction is expected between anthracyclines and PARP inhibitors?

A

Antagonism

140
Q

What impact does genetic deficiency of thiopurine methyltransferase (TPMT) have on sensitivity to mercaptopurine and 6-TG?

A

Increased toxicity in individuals with TPMT deficiency

141
Q

What is the primary toxicity of the guanine analog nalaabine?

A

Neurotoxicity

142
Q

What is the MOA of hydroxyurea?

A

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
Q

To which cell-cycle phase is the cytotoxic activity of hydroxyurea specific?

A

S phase

144
Q

As part of its catabolism, hydroxyurea is converted to what potent ribonucleotide reductase inhibitor?

A

Nitric oxide

145
Q

What enzyme is responsible for hydroxyurea degradation?

A

urease

146
Q

What is the DLT of hydroxyurea?

A

myelosuppression

147
Q

What is the oral bioavailability of hydroxyurea?

A

80-100%

148
Q

What is the route of elimination of hydroxyurea?

A

Renal

149
Q

Name 3 biological actions of vinca alkaloids outside of microtubule interaction?

A

Interference with:

  • Amino acid transport
  • DNA/RNA synthesis
  • Protein/lipid metabolism
150
Q

At what point do vincas and taxanes block mitosis?

A

metaphase/anaphase transition

151
Q

What occurs at low and high concentrations of vinca alkaloids?

A

Low conc = interference with microtubule dynamics

High conc = inhibits polymerization of tubulin

152
Q

Rank the vinca alkaloids in order of their binding affinity for tubulin.

A

Vincristine > VinBLAstine > Vinorelbine > VFL

**does NOT determine antitumor activity, but does appear to correlate to neurotoxicity

153
Q

Name 3 tissues in which ABCB1 is constitutively expressed?

A

Renal tubular epithelium, colonic mucosa, adrenal medulla

154
Q

Which of the vinca alkaloids has the longest terminal half-life?

A

Vincristine

155
Q

What is the route of elimination for all vinca alkaloids?

A

Hepatic metabolism and biliary excretion

156
Q

Characterize the degree of binding of vinca alkaloids to plasma protein and blood elements such as platelets?

A

Highly protein-bound

Bind plt and other blood elements with high affinity

157
Q

What alterations in tubulin can result in resistance to vinca alkaloids?

A 
Structural alterations in alpha and beta tubulin resulting in increased stability
Decreased expression of class III B tubulin
158
Q

In which organ does vincristine accumulate to the greatest extent?

A

Spleen

159
Q

What % of vincristine/metabolites is excreted in the urine?

A

~12%

160
Q

Which of the following drugs is more extensively concentrated in tissues: vincristine or vinblastine?

A

vinblastine

161
Q

Which of the vinca alkaloids is most lipophilic?

A

vinorelbine

162
Q

What impact might concurrent treatment with erythromycin or itraconazole have on vincristine toxicity?

A

Increased toxicity due to CYP3A inhibition

163
Q

What impact do taxanes have on intracellular tubulin concentration?

A

Decreased tubulin concentration due to stabilization of polymerized tubulin

164
Q

Which of the ABC transporters is most important in conferring taxane resistance?

A

MDR1

165
Q

What steps should be taken in the case of vincristine extravasation?

A

Heat/warm packing

SQ hyaluronidase injection

166
Q

What impact can L-spar have on vincristine clearance?

A

Decreased hepatic clearance –> increased toxicity

167
Q

What is considered the DLT of vincristine? Of the other vincas?

A

vinc - neurotox

others - myelosuppression

168
Q

Characterize the degree of protein binding by taxanes.

A

Highly protein bound

169
Q

What impact do increased levels of the beta-III tubulin isotype have on sensitivity to vincas and taxanes?

A

Taxanes - increased resistance
Vincas - increased sensitivity

B-III tubulin increases dynamic instability

170
Q

For which of the following is the affinity of taxanes higher?

a) soluble tubulin
b) polymerized tubulin

A

Polymerized tubulin

171
Q

Where is the primary taxane binding site?

A

N-terminal of B-tubulin subunit

172
Q

What factors limit oral bioavailability of taxanes, and coadministration of which drug may help mitigate this?

A

Pgp/first-pass metabolism by liver/enterocytes

Cyclosporine can help improve oral bioavailability

173
Q

What cardiac symptoms are most commonly observed in association with taxane treatment?

A

Bradyarrythmias

174
Q

How are taxanes eliminated

A

P450 metaboism and biliary/fecal excretion

<10% in urine

175
Q

MRP1 and MRP2 (ABCC1 and ABCC2) are more important in resistance to which of the microtubule-targeting agents?

A

Vincas

Limited contribution to taxane resistance

176
Q

What is the DLT of paclitaxel?

A

neutropenia

177
Q

Which infusion schedules increase the risk for paclitaxel-associated neurotoxicty?

A

short infusion schedules

178
Q

What impact do mutations in KRAS or BRAF have on sensitivity to anti-EGFR therapies?

A

Decreased sensitivity - downstream activation

179
Q

What were the two characteristics proposed as “emerging” hallmarks of cancer in Hannahan and Weinberg’s 2011 review of the hallmarks of cancer?

A

Deregulated cellular energetics

Avoiding immune destruction

180
Q

What were the original 6 characteristics proposed as the hallmarks of cancer?

A 
sustaining proliferative signaling
evading growth suppressors
enabling replicative immortality
activating invasion and metastasis
inducing angiogenesis
resisting cell death
181
Q

What is a nucleophile?

A

Electron-rich atom

182
Q

If a tumor shows resistance to a nitrogen mustard agent such as CYC, will it also exhibit resistance to a nitrosurea such as CCNU?

A

Not necessarily - nitrogen mustards and nitrosureas show only partial cross-resistance

183
Q

Alkylation by alkylating agents is nonuniform along the length of the DNA strand. Which areas of DNA are most vulnerable to alkylation?

A

Regions of active transcription

184
Q

Name two mechanisms of resistance with relevance to all alkylators?

A

glutathione inactivation

enhanced DNA repair - esp DNA alkyltransferase

185
Q

Decreased MMR results in decreased sensitivity/increased resistance to which classes of drugs?

A

5-FU
alkylators
methylators (DTIC, procarb)
platinums

186
Q

What are the most common adducts formed by alkylating agents?

A

N3 methyladenine

N7 methylguanine

187
Q

What effect does increased BER function have on tumor cell sensitivity to alkylators?

A

Decreased sensitivity

188
Q

What impact does xeroderma pigmentosum have on sensitivity to alkylating agents?

A

Increased sensitivity

Xeroderma pigmentosum = defective NER

189
Q

What happens to cyclophosphamide metabolism and half-life over time (increases or decreases) with ongoing administration?

A

Metabolism increases, half-life decreases - both CYC and ifosfamide induce their own metabolism by P450 enzymes

190
Q

How does 2-mercaptoethane sulfonate help to prevent acrolein-induced cystits without impacting anti-tumor activity?

A

MESNA dimerizes to inactive metabolite in plasma and hydrolyzes in urine to conjugate with acrolein

191
Q

Name 3 features common to all atypical alkylators/methylating agents (ie procarb, DTIC).

A

lack bifunctionality
prodrugs that require activation
contain N-methyl group

192
Q

Name 2 mechanisms of resistance that impact sensitivity to all methylating agents.

A

AGT-mediated O6 methylguanine repair

MMR deficiency

193
Q

What impact does the activity of AGT have on sensitivity to procarbazine? CCNU?

A

Decreased sensitivity/increased resistance

AGT functions in O6 methylguanine repair - increases resistance to methylators and nitrosureas

194
Q

By what route are procarb and DTIC eliminated?

A

Renal excretion

195
Q

What is the common metabolite generated by both DTIC and temozolamide under physiologic conditions?

A

MTIC –> AIC

196
Q

Which of the atypical alkylators penetrate the BBB?

A

Procarb
Temozolomide

NOT dtic

197
Q

What is the oral bioavailability of CYC, melphalan, and busulfan?

A

CYC - 100%
melphalan - 30% (variable)
busulfan >50%

198
Q

What proportion of CYC, ifosfamide, and melphalan is excreted into the urine unchanged?

A

CYC/ifos - NONE - only inactive oxidation products excreted

Melphalan - 20-35%

199
Q

What is the DLT of IV procarbazine? What is the efficacy of IV procarbazine compared to oral dosing?

A

DLT = neurotoxicity

Lack of efficacy due to need for first-pass metabolism and drug activation

200
Q

To what extent is DTIC protein-bound in plasma?

A

~20% loosely protein-bound

201
Q

What percentage of DTIC is eliminated unchanged in the urine?

A

~50%

202
Q

How is temozolomide converted to its active metabolite?

A

Spontaneous conversion on interaction with water, especially at alkaline pH >7.0

203
Q

Which enzyme constitutes the primary mechanism of resistance to temozolomide?

A

AGT

204
Q

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?

A

Greater reactivity in aqueous solution
Crosses membranes more readily
Greater toxicity

205
Q

Platinums have higher affinity for which nucleic acid? Interactions with DNA or RNA account for most of their cytotoxicty?

A

higher affinity for RNA, but most toxic effects come from DNA

206
Q

What is the predominant DNA repair pathway used to repair platinum-induced DNA lesions?

A

ds break repair (ie NHEJ, HR)

207
Q

What is amofostine?

A

A disulfide preferential activated in normal cells to scavenge free radicals – can be used to prevent cisplatin-associated neurotoxicity.

208
Q

What is the preferred solution for cisplatin injection?

A

normal saline

**avoid Mg++ containing fluids and aluminum needles as these mat inactivate cisplatin

209
Q

What is the Calvert formula for carboplatin dosing?

A

dose = target AUC * (GFR + 25)

210
Q

What DNA lesions are formed by platinums?

A

Bifunctional DNA adducts which result in kinking of DNA due to rigid bond angles

211
Q

What DNA lesions does bleomycin result in?

A

Direct DNA damage –> intercalation, ss and ds breaks

212
Q

In which phases of the cell cycle is DNA most sensitive to cleavage by bleomycin?

A

G2/M, and G1

213
Q

Is bleomycin a substrate for Pgp/MDR1?

A

no

214
Q

How is bleomycin excreted?

A

Urinary

215
Q

Name 3 factors that increase risk for bleomycin-induced pulmonary toxicity.

A
  • previous RT to chest
  • cumulative dose >450U
  • renal dysfunction
  • age
216
Q

Which cytokines are implicated in bleomycin-induced pulmonary toxicity?

A

TGF-B
TNF-a
IL-1B
IL2, 3, 4, 5, 6

217
Q

How does anthracycline dosing schedule impact efficacy? Toxicity?

A

No impact of dosing schedule on efficacy - this depends on AUC

Shorter infusion times –> greater toxicity - this depends on Cmax

218
Q

What is the MOA of dactinomycin?

A

inhibition of RNA & protein synthesis by binding to DNA

219
Q

Is dactinomycin a substrate for Pgp?

A

Yes

220
Q

What is the MOA of topotecan and ironotecan?

A

Topo-I poison - stabilizes cleavable complex

221
Q

What is the DLT of topotecan and ironotecan?

A

neutropenia, thrombocytopenia

GI/diarrhea - ironotecan&raquo_space;> topotecan

222
Q

What impact does an acidic microenvironment have of cell entry of DOX?

A

Acidic env’t –> DOX becomes ionized

If EC acidosis –> ionization and accumulation outside cell
If IC acidosis –> accumulation within cell

223
Q

How is mechlorethamine degraded?

A

Spontaneous degradation

224
Q

What are the steps in CYC metabolism?

A

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
Q

What is the most active CYC metabolite?

A

Phosphoramide mustard

226
Q

What is the major difference between CYC and ifosfamide metabolism, and how does this relate to toxicity?

A

Decloroethylation occurs much more frequently in ifosfamide (up to 25%) –> formation of neurotoxic choroacetaldehyde

227
Q

What is the primary metabolite of chorlambucil?

A

phenylacetic acid

228
Q

Why is DTIC use discouraged in cats?

A

Lack of information regarding their ability to convert the drug to active form

229
Q

What percentage of dactinomycin is excreted unchanged in urine and feces?

A

20% urine

14% feces

230
Q

What do one- and two-electron reduction of DOX result in?

A

One-electron reduction –> semiquinone free radical –> H2O2

Two-electron –> less toxic metabolites

231
Q

Why is the activity of dexrazoxane increased in cardiac myocytes compared to other tissues?

A

greatly increased conversion of prodrug to active iron chelator

232
Q

What impact do increased Bcl-2 expression and NFkB expression have on DOX sensitivity?

A

Decreased sensitivity/ increased resistance due to resistance to apoptosis (Bcl-2) and improved cellular response to stress (NFkB)

233
Q

DOX is a substrate for which efflux pumps?

A

MDR1

MRP

234
Q

What is the primary mode of DOX excretion?

A

Biliary

235
Q

What impact does paclitaxel administration have on DOX clearance?

A

delayed, likely due to Cremophor which is a substrate for Pgp

236
Q

What impact does coadministration of traztuzumab have on risk for DOX-induced cardiotoxicity?

A

increased risk

237
Q

What is the most cardiotoxic metabolite of DOX?

A

Doxorubicinol

238
Q

How do anthracyclines enter the cell?

A

Diffusion of un-ionized drug

239
Q

What impact does reduction in topoisomerase II activity have on DOX resistance?

A

decreased topo-II activity –> increased resistance to DOX & other topo-II inhibitors

240
Q

What impact would increased cellular levels of topoisomerase II have on sensitivity to etoposide?

A

Increased sensitivity

241
Q

What type of DNA breaks do topoisomerase I and III result in?

A

ssDNA breaks (Type I topoisomerases)

242
Q

What type of DNA breaks does topoisomerase II result in?

A

dsDNA breaks

243
Q

What change in etoposide dosing should be made in patients with renal dysfunction?

A

dose decrease - ~40% etoposide is eliminated by kidneys

244
Q

Does etoposide function as a radiation sensitizer?

A

yes

245
Q

What is the result of coadministration of etoposide and platinum drugs?

A

Highly synergistic

246
Q

L-spar catalyzes hydrolysis of asparagine to which end products?

A

aspartic acid + ammonia

247
Q

What impact does L-spar have on methotrexate activity?

A

terminates action of methotrexate

248
Q

What is the MOA of first-generation bisphosphonates such as etidronate and clodronate?

A

metabolized to cytotoxic analogs of ATP

249
Q

What is the MOA nitrogen-containing bisphophonates (risendronate, pamidronate, and zolendronate)?

A
  • 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
Q

Which side chain determines bisphosphonate antiresorptive potency?

A

R2 side chain

251
Q

Characterize the oral bioavailabiltiy of bisphosphonates.

A

Poor (<1%) due to calcium binding

252
Q

How are bisphosphonates metabolized and excreted?

A

they are NOT metabolized - P-C backbone is resistant to hydrolysis
excreted through kidneys

253
Q

What accounts for bisphosphonate binding to hydroxyapetite?

A

R1 side chain

254
Q

What deterines bisphosphonate-induced renal toxicity?

A

R1 side chain - related to high total dose, short infusion time, and decreased baseline renal function

255
Q

Which drugs are substrates for all 3 major drug efflux pumps (Pgp, MRP1, and BCRP)?

A

DOX/daunorubicin

methotrexate

256
Q

Vincristine, vinblastine, etoposide and paclitaxel are substrates for which drug efflux pumps?

A

Pgp

MRP1

257
Q

For which drug efflux pumps is mitoxantrone a substrate?

A

Pgp

BCRP/ABCG2

258
Q

What is the target of lapatinib?

A

HER2 + EGFR

259
Q

Which targeted therapy are nonsmoking women (especially those of Asian decent) with lung carcinoma most likely to respond to?

A

EGFR inhibitors - gefitinib and erlotinib

260
Q

What is the target for rapamycin?

A

TORC1

261
Q

What is the target of sorafenib?

A

RET, VEGFR

262
Q

Which family of kinases are the primary effectors of inflammatory cytokine receptor signaling?

A

JAK

JAK2 inhibitors are used in myeloproliferative diseases in people

263
Q

What is the target of crizotinib?

A

ALK (anaplastic lymphoma kinase)

264
Q

Activating point mutations in which gene result in the hereditary multiple endocrine neoplasia type 2?

A

RET

265
Q

What is ipilimumab?

A

anti-CTLA-4 mAb

266
Q

What toxicities limited the utility of hyaluronan cisplatin nanoconjugate in dogs with SCC?

A

Severe myelosuppression, cardiotoxicity, and ALT elevations

267
Q

What was the DLT of oral PPARg agonist rosiglitazone?

A

hepatic - ALT elevation

268
Q

What does formulation of therapeutic proteins with polyethylene glycol (PEG) achieve?

A

Increased circulating half-life

Decreased immunogenicity

269
Q

What was the MTD of PEGylated TNFa in dogs with various tumors?

A

26.7 ug/kg
DLT = vascular leak, hypotension, coagulopathy

minor/transient tumor responses noted in various tumor types

270
Q

What is valproic acid and what can be used as a pharmacodynamic biomarker for its activity?

A

HDACi
histone hyperacetylation in circulating PBMCs

**valproic acid was well tolerated in dogs, MTD not reached

271
Q

What clinical factors were associated with prolonged hospital stay in febrile neutropenic canine chemo patients?

A

tachycardia at admission
comorbidities
G-CSF use
decreasing neutrophil count after admission

272
Q

What was the mortality rate and what factors were associated with death in-hospital in febrile neutropenic canine chemo patients?

A

8.5%

hypotension, G-CSF use

273
Q

What was the rate of GI toxicity & creatinine elevation from baseline in dogs receiving piroxicam? Which factors increased risk of these toxicities?

A

GI - 84% - age and GI protectants increased risk

Creat - 73% - TCC increased risk

274
Q

What was the incidence of SHC after CYC given orally over 3 days?

A

0%

historical values - 11% for single dose, 1.4% for single + furosemide

275
Q

Increased LEs occurred in what %s of dogs receiving CCNU alone vs CCNU with denamarin?

A

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
Q

What was the response to plasmid GHRH electroporation to treat cancer-associated anemia in dogs?

A

Up to 54% had increased Hct, and responders had significantly longer survival

277
Q

How long is platinum detectable in canine urine, feces, saliva, sebum, and cerum by mass spec following administration?

A

at least 21 d

278
Q

What was the MTD of vinorelbine in cats?

A

11.5mg/m2

279
Q

What % of cats were euthanized due to toxicity in a pilot study of temozolomide +/- DOX?

A

40% :(

1 due to prolonged myelosuppression, 1 due to pleural/pericardial effusion (apparently cumulative toxicity >1300mg/m2)

280
Q

What was the rate of hepatotoxicity in cats treated with CCNU?

A

6.8%

281
Q

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?

A

23% - not thought to account for 5-FU tox

In another study, 14% of dogs with abnormal

282
Q

What was the rate of AEs in a large series of dogs treated with epirubicin?

A

36% of treatments

283
Q

What is the MTD of idarubicin in dogs >15kg?

A

22mg/m2

284
Q

What was the RR of epithelial neoplasia to oral docetaxel + CSA?

A

17%

50% RR for OSCC

285
Q

What is the MTD of Paccal Vet in dogs?

A

150mg/m2

286
Q

Dogs with MCT treated with Paccal Vet were ___x more likely to have a response than those treated with CCNU?

A

6.5X

RR = 7% (23% BRR)

287
Q

What was the MTD of a single bolus gemcitabine dose in dogs?

A

900mg/m2

Undetectable in urine at 24hrs

288
Q

Metronomic CCNU was discontinued in what % of patients due to toxicity? When was hepatotoxicity recongized?

A

27%

hepatotox at median 11d

289
Q

What % dogs developed hypertension following treatment with Palladia?

A

37%

290
Q

What was the MTD of CCNU + Palladia?

A

50mg/m2 q3wks

291
Q

What is the MTD of toceranib + piroxicam?

A

Full dose of both

292
Q

What was the ORR of canine MCT to toceranib + VBL?

A

71%

293
Q

Which combinations of bisphosphonates and chemotherapy drugs elicited synergistic killing in histiocytic sarcoma cell lines?

A

clodronate + vinc

zol + DOX

294
Q

What is the genotype of the ABCB1 polymorphism in dogs?

A

4 base-pair deletion resulting in a reading frame shift and premature stop codons

295
Q

Other than the BBB, what privileged sites does PGP participate in maintaining?

A

blood-testes barrier

placenta

296
Q

Other than the BBB, what privileged sites does BCRP (ABCG2) participate in maintaining?

A

retina - this is thought to underly fluoroquinolone-induced blindness in cats

297
Q

What is the function of feline ABCG2 compared to humans?

A

decreased

298
Q

What is the MTD of DOX in horses?

A

75mg/m2 q3wks

DLT = hypersensitivity and neutropenia

Onco Board Review (6 decks)

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